presentation of diabetic foot ulcer

Diabetic Foot Ulcers Clinical Presentation

• Author: Tanzim Khan, DPM; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
• Sections Diabetic Foot Ulcers
• Practice Essentials
• Pathophysiology
• Epidemiology
• Patient Education
• Physical Examination
• Approach Considerations
• Blood Tests
• Plain Radiography
• Computed Tomography and Magnetic Resonance Imaging
• Ankle-Brachial Index
• Pulse-Volume Recording
• Ultrasonography
• Transcutaneous Tissue Oxygen Studies
• Conventional Angiography
• Alternatives to Conventional Angiography
• Laboratory Studies
• Other Tests
• Management of Systemic and Local Factors
• Wound and Foot Care
• Surgical Care
• Options for Soft Tissue Coverage of the Clean but Nonhealing Wound
• Hyperbaric Oxygen Treatment
• Dietary Changes
• Restriction of Activity
• Measures for Prevention of Diabetic Ulcers
• Consultations
• Long-Term Monitoring
• Medication Summary
• Hemorrheologic Agents
• Antiplatelet agents
• Wound Healing Agents
• Questions & Answers
• Media Gallery

The history should focus on the signs and symptoms of a diabetic foot ulcer or pre-ulcerative lesion. Symptoms indicative of possible peripheral neuropathy or peripheral arterial insufficiency should also be investigated.

In the diagnosis of diabetic foot ulcers or pre-ulcerative lesions, the following should be taken into account:

• History of trauma
• History of puncture wound (with or without shoe gear)
• History of change in shoe gear
• History of deformity, either acquired or congenital
• History of callus or blister
• History of wound care management
• History of offloading
• Local signs of infection
• Systemic signs of infection

Symptoms of peripheral neuropathy

The symptoms of peripheral neuropathy include the following:

Hypoesthesia

Hyperesthesia

Paresthesia

Dysesthesia

Radicular pain

Symptoms of peripheral arterial insufficiency

Most people harboring atherosclerotic disease of the lower extremities are asymptomatic; others develop ischemic symptoms. Some patients attribute ambulatory difficulties to old age and are unaware of the existence of a potentially correctible problem.

Patients who are symptomatic may present with intermittent claudication, ischemic pain at rest, nonhealing ulceration of the foot, or frank ischemia of the foot.

Cramping or fatigue of major muscle groups in one or both lower extremities that is reproducible upon walking a specific distance suggests intermittent claudication. This symptom increases with ambulation until walking is no longer possible, and it is relieved by resting for several minutes. The onset of claudication may occur sooner with more rapid walking or walking uphill or up stairs.

The claudication of infrainguinal occlusive disease typically involves the calf muscles. Discomfort, cramping, or weakness in the calves or feet is particularly common in the diabetic population because they tend to have tibioperoneal atherosclerotic occlusions. Calf muscle atrophy may also occur. Symptoms that occur in the buttocks or thighs suggest aortoiliac occlusive disease.

Rest pain is less common in the diabetic population. In some cases, a fissure, ulcer, or other break in the integrity of the skin envelope is the first sign that loss of perfusion has occurred. When a diabetic patient presents with gangrene, it is often the result of infection.

Physical examination of the extremity that has a diabetic ulcer can be divided into different categories:

Examination of ulceration

Examination of the feet

Assessment of the possibility of vascular insufficiency [ 4 ]

Assessment for the possibility of peripheral neuropathy

Remember that diabetes is a systemic disease. Hence, a comprehensive physical examination of the entire patient is also vital.

Accomplish the following in examination of ulceration

• Determine the location of the ulceration, as ulcers are typically located around bony prominences and weight-bearing surfaces; typical locations include the dorsal interphalangeal joints of hammertoes and distal tips of digits, below metatarsal heads in claw toes, the medial and lateral forefoot in patients with bunions and bunionettes, plantar lateral wounds in Charcot foot, and the lateral foot and lateral malleoli in varus deformities
• Measure the size, including the depth of the wound
• Describe the wound base (granular, fibrotic, necrotic, eschar)
• Inspect for probing to bone
• Inspect for any undermining or tunneling of the wound
• Describe any drainage
• Describe the periwound area (maceration, hyperkeratotic tissue)

Examination of feet 

Carry out the following in foot examination [ 33 ] :

• Inspect the static posture of the feet on the examination table, as well as when weight-bearing.
• ​Assess for gross deformities and determine if they are reducible or rigid
• Assess ankle range of motion using the Silfverskiöld test - If there is limited ankle dorsiflexion (cannot pass neutral) with the knee both flexed and extended, it is considered gastrocsoleal tightness; if there is increased dorsiflexion with the knee flexed, however limited with the knee in extension, it is considered gastrocnemius equinus 
• Assess range of motion at the interphalangeal joints, metatarsophalangeal joints, midtarsal joints, and subtalar joints
• Evaluate muscle power of dorsiflexors, plantar flexors, invertors, and evertors to identify any muscular imbalances
• Examine the skin for dryness and fissures, as well as for discrete calluses; hemorrhagic calluses in particular are a sign of impending foot ulceration.

Assessment of possible peripheral arterial insufficiency

Physical examination discloses absent or diminished peripheral pulses below a certain level.

Although diminished common femoral artery pulsation is characteristic of aortoiliac disease, infrainguinal disease alone is characterized by normal femoral pulses at the level of the inguinal ligament and diminished or absent pulses distally. Specifically, loss of the femoral pulse just below the inguinal ligament occurs with a proximal superficial femoral artery occlusion. Loss of the popliteal artery pulse suggests superficial femoral artery occlusion, typically in the adductor canal.

Loss of pedal pulses is characteristic of disease of the distal popliteal artery or its trifurcation. However, be aware that absence of the dorsalis pedis pulse may be a normal anatomic variant that is noted in about 10% of the pediatric population. On the other hand, the posterior tibial pulse is present in 99.8% of persons aged 0-19 years. Hence, absence of both pedal pulses is a more specific indicator of peripheral arterial disease.

Other findings suggestive of atherosclerotic disease include a bruit heard overlying the iliac or femoral arteries, skin atrophy, loss of pedal hair growth, cyanosis of the toes, ulceration or ischemic necrosis, and pallor of the involved foot followed by dependent rubor after 1-2 minutes of elevation above heart level.

Assessment of possible peripheral neuropathy

Signs of peripheral neuropathy include loss of vibratory and position sense, loss of deep tendon reflexes (especially loss of the ankle jerk), trophic ulceration, foot drop, muscle atrophy, and excessive callous formation, especially overlying pressure points such as the heel.

The nylon monofilament test helps diagnose the presence of sensory neuropathy. [ 34 ] A 10-gauge monofilament nylon is pressed against each specific site of the foot just enough to bend the wire. If the patient does not feel the wire at 4 or more of these 10 sites, the test is positive for neuropathy. General use filaments can be obtained from the National Institute of Diabetes and Digestive and Kidney Diseases, or the clinician can use professional Semmes-Weinstein filaments.

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• Diabetic ulcer of the medial aspect of left first toe before and after appropriate wound care.
• Diabetic ulcer of left fourth toe associated with mild cellulitis.
• Charcot deformity with mal perforans ulcer of plantar midfoot.
• Table. Characteristics and Uses of Wound Dressing Materials
• Risk classification and follow-up based on the comprehensive foot examination [ 75 ]

Contributor Information and Disclosures

Tanzim Khan, DPM Assistant Professor of Clinical Surgery, Keck School of Medicine of the University of Southern California Disclosure: Nothing to disclose.

Vincent Lopez Rowe, MD, FACS Professor and Chief, Division of Vascular and Endovascular Surgery, Gonda (Goldschmied) Vascular Center, University of California, Los Angeles, David Geffen School of Medicine Vincent Lopez Rowe, MD, FACS is a member of the following medical societies: American College of Surgeons , American Heart Association , American Surgical Association , Pacific Coast Surgical Association , Society for Clinical Vascular Surgery , Society for Vascular Surgery , Society of Black Academic Surgeons , Society of Black Vascular Surgeons , Southern California Vascular Surgical Society , Western Vascular Society Disclosure: Nothing to disclose.

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinology , American College of Physicians , American Diabetes Association , Endocrine Society Disclosure: Nothing to disclose.

Jeffrey Lawrence Kaufman, MD Associate Professor, Department of Surgery, Division of Vascular Surgery, Tufts University School of Medicine

Jeffrey Lawrence Kaufman, MD is a member of the following medical societies: Alpha Omega Alpha , American College of Surgeons , American Society for Artificial Internal Organs , Association for Academic Surgery , Association for Surgical Education , Massachusetts Medical Society , Phi Beta Kappa , and Society for Vascular Surgery

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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• Diabetic Foot Ulcers
• Diabetic Foot Infections
• Foot Infections
• Fast Five Quiz: Do You Know What to Watch for and How Best to Treat Diabetic Foot Ulcers?
• Osteomyelitis
• Peripheral Arterial Occlusive Disease
• Fast Five Quiz: Foot Pain
• Diabetic Foot Increases the Risk for Early Death
• Diabetic Foot Infections: A Peptide's Potential Promise
• Using AI to Transform Diabetic Foot and Limb Preservation

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Diabetic Foot Ulcers

• Diabetic Foot Ulcers are very common lower extremity wounds that occur in diabetics with peripheral neuropathy and are responsible for 85% of lower extremity amputations.
• Diagnosis is made clinically with presence of a plantar foot ulcer which may probe to bone. MRI studies are useful to assess for presence and extent of osteomyelitis. 
• Treatment depends on ulcer size, ulcer thickness, ulcer location and presence of concomitant infection. 
• approximately 12% of diabetics have foot ulcers
• most common medical complication causing diabetics to get medical treatment
• foot ulcers are responsible for ~85% of lower extremity amputations
• uncontrolled hyperglycemia (Hb A1C > 8.0)
• inability to offload the affected area
• poor circulation
• poor nutrition
• serum albumin > 3.0 g/d L
• total lymphocyte count > 1,500/mm3
• has largest effect on diabetic foot pathology
• sensory dysfunction leads to lack of protective sensation and is primary risk factor for ulcer development
• autonomic dysfunction leads to drying of skin due to lack of normal glandular function
• net effect is increased mechanical and axial stress on skin that is more prone to injury due to drying
• lesser effect than neuropathy
• >60% of diabetic ulcers have decreased blood flow due to peripheral vascular disease
• 67% of ulcers that probe to bone have osteomyelitis
• usually polymicrobial
• most common pathogens are aerobic gram positive cocci (s. aureus)
• increased gram-negative organisms are found in chronic wounds and wounds recently treated with antibiotics
• obligate anaerobic pathogens with ischemia or gangrene
• deep cultures and bacterial biopsies help guide management

• often painless
• probe for bone
• look for cellulitis, pus
• check for gangrene
• improved ankle dorsiflexion with knee flexed = gastrocnemius tightness
• equivalent ankle dorsiflexion with knee flexion and extension = Achilles tightness
• assess dorsalis pedis and posterior tibialis pulses
• considered Gold Standard to assess wound healing potential
• > 30 mm Hg (or 40mmHg depending on review source cited) is a good sign of healing potential
• calcifications falsely elevate the ABI's due to decreased compliance of the calcified vessels
• index of > 0.45 and toe pressure >45mm Hg are needed to heal amputation and >60mm Hg to heal an ulcer
• AP, lateral, and oblique of foot and ankle
• best for differentiating abscess from soft tissue swelling
• difficult to differentiate infection from Charcot arthropathy on MRI
• obtain with technetium Tc99m, gallium (Ga)67, or indium (In) 111
• soft tissue infection
• osteomyelitis
• Charcot arthropathy
• angiopathic vs. neuropathic
• deep vs. superficial
• +/- osteomyelitis, antibiotics based on bone biopsy culture sensitivities
• +/- pyarthrosis
• prevention when signs of potential ulcers are present
• includes deep or wide shoes, custom insoles, rocker bottom soles, etc.
• of the available shoe only modifications, rocker sole shoes best reduce the plantar pressure on the forefoot
• medicare will cover modifications and custom shoes/insoles yearly
• first line of treatment
• provide moist environment
• absorb exudate
• act as a barrier
• off-load pressure at ulcer
• gold standard for mechanical relief plantar ulcerations
• marginal arterial supply to affected area
• patients unable to comply with cast care
• patients unable to tolerate a cast (cast claustrophobia)
• if ulcer recurs, it is typically 3-4 weeks after cast removal
• flexible toe deformities with toe ulceration  
• high rates of healing if there is no osteomyelitis on presentation
• grade 3 or greater ulcers should undergo I&D with antibiotic treatment before casting
• high rates of associated osteomyelitis if bone is able to be probed, or is exposed at the base of the ulcer
• TAL is associated with a lower risk of recurrent ulceration in plantar forefoot ulcerations
• bony prominence causing internal pressure
• several studies have shown TAL to be effective to help heal and prevent recurrence of plantar forefoot ulcers
• large heel ulcers with associated calcaneal osteomyelitis
• preserves limb length and decreases morbidity compared to higher level amputations
• forefoot gangrene and a palpable posterior tibial artery pulse
• IPJ plantar neuropathic ulcer with hypomobile/stiff MTPJ that has failed total contact casting
• often necessary for up to 4 months
• TCC followed by Charcot restraint walker then custom shoe
• alternative to TCC, same principal
• allows better wound surveillance
• significant deformity and/or extremely large girth often requires custom pneumatic walkers
• patient compliance with offloading can be an issue because the pneumatic walker is removable
• Diabetic foot ulceration is considered the most likely predictor of eventual lower extremity amputation in patients with diabetes mellitus

Technique guides are not considered high yield topics for orthopaedic standardized exams including ABOS, EBOT and RC.

• - Cavovarus Foot in Pediatrics & Adults
• Foot & Ankle
• - Diabetic Foot Ulcers
• - Amputations

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ERIC M. MATHESON, MD, MS, SCOTT W. BRAGG, PharmD, AND RUSSELL S. BLACKWELDER, MD, MDiv

Am Fam Physician. 2021;104(4):386-394

Related Letter to the Editor: Caution Before Antibiotic De-escalation Following Negative MRSA Nares Testing 

Patient information: See related handout on preventing diabetic foot infections .

Author disclosure: No relevant financial affiliations.

Diabetes-related foot infections occur in approximately 40% of diabetes-related foot ulcers and cause significant morbidity. Clinicians should consider patient risk factors (e.g., presence of foot ulcers greater than 2 cm, uncontrolled diabetes mellitus, poor vascular perfusion, comorbid illness) when evaluating for a foot infection or osteomyelitis. Indicators of infection include erythema, induration, tenderness, warmth, and drainage. Superficial wound cultures should be avoided because of the high rate of contaminants. Deep cultures obtained through aseptic procedures (e.g., incision and drainage, debridement, bone culture) help guide treatment. Plain radiography is used for initial imaging if osteomyelitis is suspected; however, magnetic resonance imaging or computed tomography may help if radiography is inconclusive, the extent of infection is unknown, or if the infection orientation needs to be determined to help in surgical planning. Staphylococcus aureus and Streptococcus agalactiae are the most commonly isolated pathogens, although polymicrobial infections are common. Antibiotic therapy should cover commonly isolated organisms and reflect local resistance patterns, patient preference, and the severity of the foot infection. Mild and some moderate infections may be treated with oral antibiotics. Severe infections require intravenous antibiotics. Treatment duration is typically one to two weeks and is longer for slowly resolving infections or osteomyelitis. Severe or persistent infections may require surgery and specialized team-based wound care. Although widely recommended, there is little evidence on the effectiveness of primary prevention strategies. Systematic assessment, counseling, and comorbidity management are hallmarks of effective secondary prevention for diabetes-related foot infections.

Diabetes-related foot infections form in approximately 40% of foot ulcers in patients with diabetes mellitus. 1 Infections can rapidly progress to cellulitis, abscess formation, osteomyelitis, and necrotizing fasciitis. In 2016, diabetes-related foot infections contributed to more than 130,000 lower-extremity amputations in the United States. 2 The five-year mortality rate following amputation is approximately 50%, exceeding the mortality rate of many cancers. 3

Pathophysiology

Patients with diabetes and vascular compromise, peripheral neuropathy, and impaired immune function are at high risk of developing foot infections. The risk increases with deformities (e.g., bunions, hammer toe, Charcot foot) that result in high compressive forces in certain areas of the foot. 4 Peripheral neuropathy causes the loss of protective sensation for pain and temperature and increases the risk of foot trauma and ultimately foot ulceration. Approximately 50% of patients with neuropathy are asymptomatic, making recognition of a patient with an ulcer difficult. 5 When the skin ulcerates, an infection can develop rapidly because of circulatory compromise and an impaired immune response. Infection can spread rapidly to surrounding tissues, initially causing cellulitis and later more severe complications such as osteomyelitis and necrotizing fasciitis. 6

Microbiology

The most commonly isolated organisms from diabetes-related foot infections are the gram-positive bacteria Staphylococcus aureus , Staphylococcus epidermidis , Streptococcus agalactiae (i.e., group B Streptococcus ), and Enterococcus species. Wounds infected by methicillin-resistant S. aureus (MRSA) occur in approximately 15% of cases and are more serious considering the virulence of MRSA and the limited number of treatment options. 7 Gram-negative bacteria are common and isolated in more than one-half of samples, particularly the Enterobacteriaceae group and Pseudomonas aeruginosa . 8 Anaerobes are present in about one-third of cultures. Bacteroides fragilis , Prevotella , Porphyromonas , and Clostridium species are the most common. 9 Approximately 50% to 80% of infections are polymicrobial, which complicates treatment. 10

Diagnostic Evaluation

Prompt diagnosis of a diabetes-related foot infection decreases the risk of morbidity and mortality. Family physicians should consider patient risk factors (e.g., presence of foot ulcers greater than 2 cm, uncontrolled diabetes, poor vascular perfusion, comorbid illness) when assessing for infection. Findings suggestive of infection include erythema, induration, tenderness, warmth, and drainage. The probe-to-bone test is an office maneuver that is 87% sensitive and 83% specific for osteomyelitis. 11 A probe-to-bone test result is positive if insertion of a sterile and blunt metal instrument is met with hard or gritty resistance. An erythrocyte sedimentation rate greater than 70 mm per hour is also suggestive of osteomyelitis. 4 , 6 Other causes of inflammation (e.g., gout, rheumatoid arthritis, trauma) should be clinically ruled out.

Although an elevated white blood cell count can indicate a more severe infection, it is not often elevated with a diabetes-related foot infection. C-reactive protein and procalcitonin correlate better to soft tissue bacterial infections than erythrocyte sedimentation rate and white blood cell count. 6 Routine superficial wound cultures should be avoided because of the high rate of contaminants; however, deep tissue cultures obtained using aseptic procedures (i.e., incision and drainage, debridement, and bone culture) help guide treatment. 6 , 12 A negative MRSA nares culture reduces the likelihood that a diabetes-related foot infection is caused by MRSA. Studies have shown correlations with negative predictive values between 73% and 90%. 13 , 14

Plain radiography should be the initial imaging test if osteomyelitis is suspected. 6 , 15 Osteomyelitis can take weeks to appear on radiographs; therefore, magnetic resonance imaging (MRI) or computed tomography (CT) is warranted if a concern for osteomyelitis persists with normal radiography findings. MRI helps detect soft tissue involvement and identifies the spatial orientation of infection to guide surgical planning. CT is appropriate if MRI is contraindicated. 15

Vascular assessment should be performed on presentation, and patients with nonpalpable pulses should be formally evaluated for arterial insufficiency. 16 Approximately 10% to 40% of people with diabetes have peripheral arterial disease. 17 An ankle-brachial index is a quick and affordable way to assess blood flow, but it can be inaccurate because of arterial calcification with diabetes. 16 , 18 Transcutaneous oximetry or arterial duplex ultrasonography may improve the accuracy of the vascular assessment. 17 , 19 For more urgent detection of arterial disease, magnetic resonance angiography with and without intravenous contrast media or a CT with intravenous contrast media is preferred. If a patient is unable to receive intravenous contrast media because of renal disease, duplex ultrasonography of the lower extremity or magnetic resonance angiography without contrast media are appropriate alternatives. 20

GRADING SEVERITY

In 2019, the International Working Group on the Diabetic Foot published an update to the grading severity scale for diagnosing and classifying the extent of diabetes-related foot infections. This scale is the most validated scoring system to grade the severity of the infection and is summarized in Table 1 . 6 The scale scores a foot ulcer from 1 to 4 (1 = uninfected, 2 = mild infection, 3 = moderate infection, 4 = severe infection) and an “(O)” may follow scores 3 or 4 to indicate osteomyelitis.

Erythema from a diabetes-related foot infection does not have to be contiguous to a foot ulcer in the updated classification scheme. 6 Scores of 3 (odds ratio [OR] = 1.7) or 4 (OR = 2.5) are associated with increased amputation rates. 21 Other validated tools include the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth scoring system and the Wound, Ischemia, foot Infection scale, which help predict outcomes and guide decisions for surgical interventions. 18 , 22 The Perfusion, Extent, Depth, Infection, and Sensation score is a validated scale to predict amputation and mortality at six months and is available as an online calculator ( https://www.mdcalc.com/pedis-score-diabetic-foot-ulcers ). 23 , 24 Figure 1 shows an uninfected ulcer, and Figure 2 shows an infected diabetes-related foot ulcer.

ANTIBIOTIC THERAPY

Clinicians choosing antibiotics to treat patients with a diabetes-related foot infection should consider local antimicrobial sensitivities, the severity of infection, patient factors (e.g., drug-drug interactions, drug-disease interactions, renal dysfunction, drug allergies), previous antibiotic response, and patient preference. It is unclear if any one antibiotic is superior for resolving an infection or safer than other antibiotics. 25 Empiric antibiotic coverage for a mild infection should include S. aureus and S. agalactiae . 6 Guidelines also recommend empiric coverage for MRSA. A negative MRSA nares culture may help clinicians de-escalate MRSA-specific coverage considering the high negative predictive value of this test. 6 , 13 , 14 Empiric antibiotic coverage for gram-negative rods (including P. aeruginosa ) and anaerobes is reserved for moderate or severe infections, recurrent infections, or infections with severe limb ischemia. 6 Antibiotics used to treat diabetes-related foot infections are summarized in Table 2 . 26 – 28

Oral antibiotics are appropriate for individuals with mild infection and some moderate infections, whereas intravenous antibiotics are always needed initially for a severe infection, including individuals with osteomyelitis. 4 , 6 After the infection improves on intravenous antibiotics, it is reasonable to switch to an oral antibiotic. Oral antibiotics can also be used for osteomyelitis after five to seven days of intravenous coverage if the oral regimen has a high bioavailability. 6

The optimal duration of antibiotic therapy for a diabetes-related foot infection depends on how quickly the infection improves, the severity of infection, and patient factors (e.g., peripheral vascular disease, antibiotic adherence, adverse antibiotic effects). 29 Most patients should receive one to two weeks of antibiotics; however, treatment could be extended to three to four weeks for slowly resolving infections. 4 , 6 Antibiotics may be needed for only a few days if osteomyelitis is surgically treated with amputation. Guidelines have recommended four to six weeks of antibiotics if osteomyelitis is not treated surgically, but recent evidence suggests three weeks of therapy may be similar to six weeks. 4 , 6 , 30

Topical antibiotics are commonly applied to dressings for the prevention and treatment of mild diabetes-related foot infections. Resolution of a foot infection may be faster with this approach, although the data supporting topical antibiotics is weak and based on poorly designed trials. 31

SURGICAL TREATMENT

Surgical treatment plays a significant role in the management of diabetes-related foot infection. Tissue and bone cultures obtained during surgical interventions help guide antibiotic selection. Many patients need sharp surgical debridement by a wound care clinician or surgeon to remove necrotic tissue or calluses and aid in the formation of granulation tissue capable of re-epithelialization. 6 Shared decision-making with patients is important because surgical procedures range from bedside debridement to major amputation. Amputations are devastating psychologically, and many patients fear amputation more than death. 32

Surgical intervention is needed for gangrene, necrotizing fasciitis, or significant abscess formation. Although surgical resection of osteomyelitis was traditionally the standard of care, emerging evidence suggests most infections respond well to antibiotic therapy alone. 6

In patients with a diabetes-related foot infection and ischemia, vascular interventions should be considered to improve a patient's treatment response and lower the risk of recurrence. 17 The Wound, Ischemia, foot Infection score predicts clinical outcomes and guides interventions in patients with more advanced disease. 33 , 34 The Wound, Ischemia, foot Infection scoring system factors in the International Working Group on the Diabetic Foot infection grade, objective measures to determine the extent of ischemia, and the anticipated likelihood of wound healing. These factors combine to stage wounds from 0 to 3 with higher scores requiring more invasive surgical management, including amputation. 18

OTHER THERAPIES

Wound therapy in a patient with a diabetes-related foot infection is complex and often requires team-based care. Comprehensive wound care may include debridement, application of moist dressings, and the use of off-loading orthotics to reduce pressure on a wound. 6 A moist dressing is preferred to aid in healing and help with infection control. It is unknown if any specific dressing is more effective because of a lack of head-to-head trials. 35 Redistribution of pressure off the plantar surface is important because this is the main cause of foot ulcers and, if not addressed, may inhibit ulcer healing. Strategies to help with off-loading pressure include changes to a patient's shoes, specialized boots, or orthotic walkers. 36

Studies of adjunctive treatments (e.g., hyperbaric oxygen therapy, maggot debridement therapy, granulocyte colony-stimulating factors, topical oxygen therapy, laser therapy) for healing diabetes-related foot ulcers have mixed results. Of these alternative treatments, hyperbaric oxygen therapy has the best data, with evidence showing that it lowers the risk of major amputations and improves wound healing; however, evidence does not support reductions in minor amputations or mortality. 37 Maggot debridement therapy has good data, with evidence for shortening ulcer healing time and reducing the rate of amputations. 38 Granulocyte colony-stimulating factors have not been shown to help resolve an infection or foot ulcer significantly, but they may decrease the risk of surgical interventions and amputations. 39 Promising evidence exists for topical oxygen therapy and laser therapy for improving diabetes-related foot ulcer healing; however, more evidence is needed on patient-oriented outcomes before widespread adoption of either intervention. 40 , 41

Little evidence exists for primary prevention strategies of diabetes-related foot ulcers or infections despite widespread support for these interventions. 42 Guidelines strongly support systematic assessment, foot care counseling, and comorbidity management for primary prevention because these strategies are useful in secondary prevention, and complications from a diabetes-related foot infection are significant. 6 , 43 Recognition of a patient with neuropathy is critical considering the high rate of patients who are asymptomatic. Conducting a foot examination may take only three minutes and can be organized into three parts (patient history, physical examination, patient education). 5 Team-based care for primary prevention may include nurses, pharmacists, podiatrists, and other clinicians.

Secondary prevention of diabetes-related foot ulcers and infections starts with frequent, systematic assessments recommended by guidelines such as the American Diabetes Association's Standards of Medical Care. These guidelines highlight the importance of a comprehensive foot examination at least annually, and for every diabetes care visit for individuals at high risk of an infection (e.g., poor circulation, history of amputation, severe neuropathy). 43 All patients with diabetes should receive counseling on foot care and how to choose appropriate footwear. Using therapeutic footwear is often unnecessary; however, it should be considered in high-risk patients (e.g., severe neuropathy, foot deformities, ulcers, poor circulation, history of amputation). 43

Other preventive techniques include improving glucose control, smoking cessation, daily foot inspection, debridement of calluses, and monthly physician foot checks for patients with end-stage renal disease requiring dialysis. 42 – 45 Interventions to prevent an ulcer or diabetes-related foot infections are summarized in Table 3 . 5 , 42 – 45

This article updates previous articles on this topic by Gemechu, et al. , 27 and Bader . 26

Data Sources: A PubMed search was completed in Clinical Queries using the key terms diabetic foot ulcers, infections, antibiotics, statistics, pharmacological, and prevention. The search included meta-analyses, randomized controlled trials, clinical trials, and reviews. Also searched were Access Medicine, the Cochrane Library, Lexicomp, the National Guideline Clearinghouse database, and UpToDate. Search dates: October 27, 2020 to November 4, 2020, and April 26, 2021.

Figure 1 and Figure 2 provided courtesy of Joshua Visserman, MD.

• Jia L, Parker CN, Parker TJ, et al.; Diabetic Foot Working Group, Queensland Statewide Diabetes Clinical Network (Australia). Incidence and risk factors for developing infection in patients presenting with uninfected diabetic foot ulcers. PLoS One. 2017;12(5):e0177916.

Centers for Disease Control and Prevention. National diabetes statistics report, 2020. Accessed October 20, 2020. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf

• Armstrong DG, Swerdlow MA, Armstrong AA, et al. Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer. J Foot Ankle Res. 2020;13(1):16.
• Lipsky BA, Berendt AR, Cornia PB, et al.; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54(12):e132-e173.
• Miller JD, Carter E, Shih J, et al. How to do a 3-minute diabetic foot exam [published correction appears in J Fam Pract . 2015;64(8):452]. J Fam Pract. 2014;63(11):646-656.
• Lipsky BA, Senneville É, Abbas ZG, et al.; International Working Group on the Diabetic Foot (IWGDF). Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36(suppl 1):e3280.
• Reveles KR, Duhon BM, Moore RJ, et al. Epidemiology of methicillin-resistant Staphylococcus aureus diabetic foot infections in a large academic hospital: implications for antimicrobial stewardship. PLoS One. 2016;11(8):e0161658.
• Henig O, Pogue JM, Cha R, et al. Epidemiology of diabetic foot infection in the metro-Detroit area with a focus on independent predictors for pathogens resistant to recommended empiric antimicrobial therapy. Open Forum Infect Dis. 2018;5(11):ofy245.
• Citron DM, Goldstein EJ, Merriam CV, et al. Bacteriology of moderate-to-severe diabetic foot infections and in vitro activity of antimicrobial agents. J Clin Microbiol. 2007;45(9):2819-2828.
• Sadeghpour Heravi F, Zakrzewski M, Vickery K, et al. Bacterial diversity of diabetic foot ulcers: current status and future prospectives. J Clin Med. 2019;8(11):1935.
• Lam K, van Asten SAV, Nguyen T, et al. Diagnostic accuracy of probe to bone to detect osteomyelitis in the diabetic foot: a systematic review. Clin Infect Dis. 2016;63(7):944-948.

Chakraborti C, Le C, Yanofsky A. Sensitivity of superficial cultures in lower extremity wounds. J Hosp Med. 2010;5(7):415-420.

• Acquisto NM, Bodkin RP, Brown JE, et al. MRSA nares swab is a more accurate predictor of MRSA wound infection compared with clinical risk factors in emergency department patients with skin and soft tissue infections. Emerg Med J. 2018;35(6):357-360.
• Mergenhagen KA, Croix M, Starr KE, et al. Utility of methicillin-resistant Staphylococcus aureus nares screening for patients with a diabetic foot infection. Antimicrob Agents Chemother. 2020;64(4):e02213-e02219.
• Walker EA, Beaman FD, Wessell DE, et al.; Expert Panel on Musculoskeletal Imaging. ACR appropriateness criteria. Suspected osteomyelitis of the foot in patients with diabetes mellitus. J Am Coll Radiol. 2019;16(11S):S440-S450.

Bandyk DF. The diabetic foot: pathophysiology, evaluation, and treatment. Semin Vasc Surg. 2018;31(2–4):43-48.

Hart T, Milner R, Cifu A. Management of the diabetic foot. JAMA. 2017;318(14):1387-1388.

• Mills JL, Conte MS, Armstrong DG, et al.; Society for Vascular Surgery Lower Extremity Guidelines Committee. The Society for Vascular Surgery Lower Extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot infection (WIfI). J Vasc Surg. 2014;59(1):220-234.e1–2.

Fagher K, Katzman P, Löndahl M. Transcutaneous oxygen pressure as a predictor for short-term survival in patients with type 2 diabetes and foot ulcers: a comparison with ankle-brachial index and toe blood pressure. Acta Diabetol. 2018;55(8):781-788.

• Ahmed O, Hanley M, Bennett SJ, et al.; Expert Panel on Vascular Imaging. ACR appropriateness criteria. Vascular claudication-assessment for revascularization. J Am Coll Radiol. 2017;14(5S):S372-S379.

Sen P, Demirdal T, Emir B. Meta-analysis of risk factors for amputation in diabetic foot infections. Diabetes Metab Res Rev. 2019;35(7):e3165.

• Ince P, Abbas ZG, Lutale JK, et al. Use of the SINBAD classification system and score in comparing outcome of foot ulcer management on three continents. Diabetes Care. 2008;31(5):964-967.
• Chuan F, Tang K, Jiang P, et al. Reliability and validity of the perfusion, extent, depth, infection and sensation (PEDIS) classification system and score in patients with diabetic foot ulcer. PLoS One. 2015;10(4):e0124739.

Chuan F. PEDIS score for diabetic foot ulcers. MDCalc. Accessed December 30, 2020. https://www.mdcalc.com/pedis-score-diabetic-foot-ulcers

• Selva Olid A, Solà I, Barajas-Nava LA, et al. Systemic antibiotics for treating diabetic foot infections. Cochrane Database Syst Rev. 2015;(9):CD009061.

Bader MS. Diabetic foot infection. Am Fam Physician. 2008;78(1):71-79. Accessed April 6, 2021. https://www.aafp.org/afp/2008/0701/p71.html

Gemechu FW, Seemant F, Curley CA. Diabetic foot infections. Am Fam Physician. 2013;88(3):177-184. Accessed April 6, 2021. https://www.aafp.org/afp/2013/0801/p177.html

Lexicomp. Accessed October 27, 2020. https://online.lexi.com/lco/action/login

• Dudareva M, Kümin M, Vach W, et al. Short or long antibiotic regimes in orthopaedics (SOLARIO): a randomised controlled open-label non-inferiority trial of duration of systemic antibiotics in adults with orthopaedic infection treated operatively with local antibiotic therapy. Trials. 2019;20(1):693.
• Gariani K, Pham TT, Kressmann B, et al. Three versus six weeks of antibiotic therapy for diabetic foot osteomyelitis: a prospective, randomized, non-inferiority pilot trial. Clin Infect Dis. 2020; ;ciaa1758.
• Dumville JC, Lipsky BA, Hoey C, et al. Topical antimicrobial agents for treating foot ulcers in people with diabetes. Cochrane Database Syst Rev. 2017;(6):CD011038.

Wukich DK, Raspovic KM, Suder NC. Patients with diabetic foot disease fear major lower-extremity amputation more than death. Foot Ankle Spec. 2018;11(1):17-21.

• Zhan LX, Branco BC, Armstrong DG, et al. The Society for Vascular Surgery lower extremity threatened limb classification system based on wound, ischemia, and foot infection (WIfI) correlates with risk of major amputation and time to wound healing. J Vasc Surg. 2015;61(4):939-944.

Peripheral Vascular Diagnosis Made Intelligent. WIfI classification system. Accessed December 30, 2020. https://www.perimed-instruments.com/content/wifi-classification-system/

• Vas P, Rayman G, Dhatariya K, et al. Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review. Diabetes Metab Res Rev. 2020;36(suppl 1):e3284.

Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018;1411(1):153-165.

• Sharma R, Sharma SK, Mudgal SK, et al. Efficacy of hyperbaric oxygen therapy for diabetic foot ulcer, a systematic review and meta-analysis of controlled clinical trials. Sci Rep. 2021;11(1):2189.
• Sun X, Jiang K, Chen J, et al. A systematic review of maggot debridement therapy for chronically infected wounds and ulcers. Int J Infect Dis. 2014;25:32-37.
• Cruciani M, Lipsky BA, Mengoli C, et al. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database Syst Rev. 2013;(8):CD006810.

Thanigaimani S, Singh T, Golledge J. Topical oxygen therapy for diabetes-related foot ulcers: a systematic review and meta-analysis. Diabet Med. 2021;:e14585.

Huang J, Chen J, Xiong S, et al. The effect of low-level laser therapy on diabetic foot ulcers: a meta-analysis of randomised controlled trials. Int Wound J . March 9, 2021. Accessed April 25, 2021. https://onlinelibrary.wiley.com/doi/epdf/10.1111/iwj.13577

• van Netten JJ, Price PE, Lavery LA, et al.; International Working Group on the Diabetic Foot. Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32(suppl 1):84-98.
• American Diabetes Association. Microvascular complications and foot care: standards of medical care in diabetes–2020. Diabetes Care. 2020;43(suppl 1):S135-S151.
• Xiang J, Wang S, He Y, et al. Reasonable glycemic control would help wound healing during the treatment of diabetic foot ulcers. Diabetes Ther. 2019;10(1):95-105.
• Marn Pernat A, Peršič V, Usvyat L, et al. Implementation of routine foot check in patients with diabetes on hemodialysis: associations with outcomes. BMJ Open Diabetes Res Care. 2016;4(1):e000158.

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Presentation, etiology, and characterization of diabetic foot ulcers, wound classification and staging, epidemiology of diabetic foot ulcers, risk factors for dfu and associated morbidity, morbidity and mortality related to dfu, economic burden of dfu, primary and secondary prevention of dfu, quality of life and functional impact of dfu, conclusions, article information, etiology, epidemiology, and disparities in the burden of diabetic foot ulcers.

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Katherine McDermott , Michael Fang , Andrew J.M. Boulton , Elizabeth Selvin , Caitlin W. Hicks; Etiology, Epidemiology, and Disparities in the Burden of Diabetic Foot Ulcers. Diabetes Care 2 January 2023; 46 (1): 209–221. https://doi.org/10.2337/dci22-0043

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Diabetic foot ulcers (DFU) are a major source of preventable morbidity in adults with diabetes. Consequences of foot ulcers include decline in functional status, infection, hospitalization, lower-extremity amputation, and death. The lifetime risk of foot ulcer is 19% to 34%, and this number is rising with increased longevity and medical complexity of people with diabetes. Morbidity following incident ulceration is high, with recurrence rates of 65% at 3–5 years, lifetime lower-extremity amputation incidence of 20%, and 5-year mortality of 50–70%. New data suggest overall amputation incidence has increased by as much as 50% in some regions over the past several years after a long period of decline, especially in young and racial and ethnic minority populations. DFU are a common and highly morbid complication of diabetes. The pathway to ulceration, involving loss of sensation, ischemia, and minor trauma, is well established. Amputation and mortality after DFU represent late-stage complications and are strongly linked to poor diabetes management. Current efforts to improve care of patients with DFU have not resulted in consistently lower amputation rates, with evidence of widening disparities and implications for equity in diabetes care. Prevention and early detection of DFU through guideline-directed multidisciplinary care is critical to decrease the morbidity and disparities associated with DFU. This review describes the epidemiology, presentation, and sequelae of DFU, summarizes current evidence-based recommendations for screening and prevention, and highlights disparities in care and outcomes.

Graphical Abstract

Diabetic foot ulcers (DFU) are a common, highly morbid consequence of longstanding and poorly managed diabetes. Of the estimated 537 million people worldwide who have diabetes ( 1 ), 19% to 34% will develop a DFU in their lifetime ( 2 ). Approximately 20% of people who develop a DFU will require lower-extremity amputation, either minor (below the ankle), major (above the ankle), or both ( 2 ), and 10% will die within 1 year of their first DFU diagnosis ( 3 , 4 ). The purpose of this review is to describe the presentation and epidemiology of DFU and its associated complications, including a discussion of disparities in DFU presentation and outcomes.

A DFU is defined as a break of the epidermis and at least part of the dermis in a person with diabetes. More superficial or closed lesions that do not penetrate to dermis (e.g., callous, blister, warmth, or erythema) are characterized as preulcerative but are at high risk of progression to ulcer ( Fig. 1A ) ( 5 ). Repetitive minor trauma causes ulcer formation in most cases ( 6 ), typically as a result of elevated pressure at plantar weightbearing sites, friction and shearing due to poorly fitting shoes or gait abnormalities, or an unrecognized injury sustained on an insensate foot (e.g., puncture wounds, burns, or ingrown toenails) ( 6 ). Structural deformities, such as Charcot neuroarthropathy, confer additional risk of DFU ( 2 ). Following a minor traumatic event, complex and multifactorial pathways ultimately lead to ulceration ( Fig. 2 ) ( 6 , 7 ).

Characteristic examples of preulcerative ( A ), neuropathic ( B and C ), neuroischemic ( D–F ), and ischemic ( H–I ) DFU.

Person- and foot-specific factors interact to promote DFU risk and poor clinical outcomes.

The underlying etiology of DFU is classified into three types: purely neuropathic (35%), purely ischemic (15%), and mixed neuroischemic (50%) ( 8 ). These classifications are based on the presence or absence of peripheral neuropathy (PN) and associated sensory loss (neuropathic), peripheral artery disease (PAD) (ischemic), or both (neuroischemic) ( 8 , 9 ). Classic neuropathic ulcers present as painless, “punched out” round ulceration on the weightbearing surfaces of the foot with raised, macerated, or undermined margins and thick surrounding callous ( Fig. 1B and C ). Ischemic or neuroischemic ulcers are characteristically irregular lesions, often with a pale or necrotic base, sometimes presenting as gangrene ( 8 ), or round ulcerations at points of ischemia and friction, such as the dorsal surfaces of toe joints. Ischemic and neuroischemic ulcers are more likely than purely neuropathic ulcers to present as larger ulcers, midfoot ulcers, or hindfoot ulcers and to present with cellulitis, abscess, or osteomyelitis ( Fig. 1D–I ) ( 7 ). The prevalence of both PN and PAD increases with age, duration of diabetes, and higher HbA 1c , and neuroischemic ulcers comprise an increasing proportion of DFU as the longevity of diabetes patients increases ( 7 , 10 ).

Peripheral Neuropathy

Diabetic PN is a heterogenous clinical entity but is broadly defined as any constellation of signs or symptoms of peripheral nerve dysfunction without another clear cause, presumed to be the result of both metabolic and vascular factors in the setting of chronic hyperglycemia ( 11 ). PN most often presents a symmetric polyneuropathy that is characterized by pain and paresthesia, or is asymptomatic in up to 50% of cases, along with sensory, motor, and autonomic deficits ( 11 , 12 ). Each of these deficits contributes to DFU occurrence.

Sensory neuropathy leads to loss of proprioception, pain, and temperature sensation (together called loss of protective sensation), which predisposes to unrecognized minor trauma and contributes to abnormal gait ( 8 , 12 ). Preulcerative lesions or minor wounds remain unnoticed and are repeatedly retraumatized, resulting in ulcer formation and, often, in delayed diagnosis of incident or recurrent ulcers. Motor neuropathy precipitates muscle wasting, which tends to preferentially affect extensors ( 8 ). The resulting flexor-extensor imbalance leads to foot deformities (equinus deformity, clawed toes), abnormal gait, and consequently abnormal pressure distribution that predisposes new pressure points to ulceration ( Fig. 2 ). Autonomic neuropathy results in reduced sweating that causes dry, fragile skin prone to spontaneous cracking, reduced sympathetic nerve–induced vasoconstriction, and microvascular dysregulation of the skin that contributes to local edema and ultimately impaired healing ( 12 ).

The diagnosis of PN often requires dedicated sensory and monofilament testing, and even these can fail to diagnose mild neuropathy, especially when performed by untrained providers. The lifetime prevalence of PN in adults with diabetes is estimated to be at least 50% ( 12 ), and neuropathy of any kind confers an approximate sevenfold risk of DFU ( 12 ).

Peripheral Artery Disease

PAD is a narrowing or blockage of blood vessels in the extremities, usually the lower extremities, that results in decreased perfusion ( 13 ). Chronic limb-threatening ischemia is the clinical syndrome of end-stage PAD in which resting perfusion needs are unmet, and it manifests as rest pain and/or tissue loss ( 13 ). Diabetes is strongly associated with the development and acceleration of PAD ( 13 , 14 ) and leads to a unique PAD phenotype ( 8 , 15 ).

PAD in people with diabetes differentially affects the infrapopliteal arteries but also affects the iliac and femoral arteries at rates similar to those of adults without diabetes ( 15 ). PAD in people with diabetes is more likely to be diffuse and to present with long-segment arterial occlusions (rather than stenosis) compared with PAD in adults without diabetes ( 8 , 13 ) and is characterized by medial arterial calcification, as opposed to the intraluminal atherosclerosis typical of nondiabetic PAD ( 13 , 16 ).

PAD in adults with diabetes poses unique diagnostic challenges. Limited activity and PN may obscure symptoms of PAD ( 8 , 13 ). Additionally, medial calcification makes the standard ankle–brachial index unreliable due to noncompressible vessels, and toe pressures and/or toe cutaneous oxygenation are necessary adjuncts to evaluate PAD in these patients ( 8 , 13 , 16 ). PAD is likely underdiagnosed as a result, but lifetime prevalence of diagnosed PAD in diabetes is 20% to 50% ( 14 ). PAD is a contributing factor in 50% to 70% of DFU and is a significant risk factor for delayed wound healing, infection, amputation (here, and below where not specified, this includes both minor and major lower-extremity amputation), and mortality in both type 1 and type 2 diabetes ( 7 , 17 , 18 , 19 ).

DFU comprise a wide spectrum of disease severity and acuity. Salient wound- and foot-specific factors considered in the evaluation of DFU are wound size and depth, presence and severity of infection, presence of PN or PAD, and ulcer location ( 20 ). Classification systems aim to standardize wound evaluation, communicate wound and patient characteristics between providers and across time, guide prognostication and clinical decision-making, and facilitate generalizable research on interventions and outcomes. There are several classification schemas frequently applied to DFU ( Table 1 ), but no prevailing gold standard exists ( 20 , 21 ). Available resources, patient population, practice setting, and intended use generally determine which classification system is applied ( 20 ). One recently developed system widely used in multidisciplinary diabetic foot care settings is the Society Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system ( Table 1 ) ( 21 ), which, in addition to characterizing and risk stratifying DFU, was designed to guide clinical decision-making about the potential benefit of revascularization ( Fig. 3 ). WIfI has been extensively validated and has prognostic utility for outcomes including wound healing rates and risk of amputation ( 21 , 22 ).

Society for Vascular Surgery WIfI classification, amputation risk stratification, and benefit of revascularization. Adapted from Mills et al. ( 21 ).

Description and summary of benefits and limitations for common existing diabetic foot and limb classification systems

IWGDF, International Working Group on the Diabetic Foot, an international panel of experts including podiatrists, diabetologists, infectious disease specialists, and surgeons; LEA, lower-extremity amputation; LOPS, loss of protective sensation.

Incidence and Prevalence of DFU

Reported incidence of DFU varies widely depending on the study design, the population, and the era. In series since 2010, annual incidence generally ranges from 0.2% to 11% in diabetes-specific clinical settings ( 10 , 23 – 26 ) or from less than 0.1% to 8% in community- and population-based cohorts ( 10 , 17 , 27 , 28 ). Recent data on relative incidence in type 1 versus type 2 diabetes are conflicting ( 10 , 17 ), and differences in DFU risk between populations of type 1 and type 2 diabetes will be strongly determined by differences in age and duration of diabetes.

The International Diabetes Foundation estimates that 40 million to 60 million people globally are affected by DFU ( 1 ), a marked increase from 2015 estimates that ranged from 9 million to 26 million. Like incidence, prevalence estimates vary widely and are influenced by differences in definitions of DFU, the approach to surveillance, completeness of follow-up, and the definition of and approach to defining diabetes (denominator) ( 29 ). A recent meta-analysis found a 6.3% global prevalence of DFU among adults with diabetes ( 30 ), which equates to approximately 33 million people affected by DFU. While DFU has historically been reported at the highest rates in North America ( 30 ), modern cohort studies find rates upwards of 15% in populations of people with diabetes in Africa and South America. The global prevalence of DFU is reported to be lower in adults with type 1 compared with type 2 diabetes ( 30 ), which may reflect younger age and cumulative duration, differences in study design and data collection, and/or lack of representative cohorts of people with type 1 diabetes.

Patterns of DFU prevalence have remained stable despite fluctuations in incidence ( 4 ). Persistence of long healing times and one-year recurrence rates above 20% have not improved in the past 15–20 years despite advances in wound care and revascularization techniques ( 31 ). The lifetime risk of DFU has been frequently reported in the range of 12% to 25% ( 30 ), although a recent report by Armstrong et al. ( 2 ) suggests lifetime risk is higher (between 19% and 34%) as a result of increases in estimated life expectancy. There is a relative paucity of high-quality population-based studies of DFU incidence and prevalence. More community-based large-scale epidemiologic studies are needed to better characterize the frequency, clinical course, and risk factors for DFU, but clinical and demographic factors that have been strongly associated with DFU in the existing literature will be reviewed here.

Both patient- and foot-specific factors contribute to the risk of DFU ( Fig. 2 ) ( 22 ). The concept of the “at-risk foot,” which requires higher-intensity screening and surveillance for DFU, is an increasing focus of research and guideline-based care ( 16 , 32 ). Demographic, socioeconomic, and access-to-care factors are also strongly related to DFU and its complications ( 33 – 36 ). Studies including adults with both type 1 and type 2 diabetes suggest that risk factors for DFU are similar ( 17 ), and the factors described below apply to both type 1 and type 2 diabetes unless otherwise stated.

The risk of DFU increases with age, which is closely related to longer duration of diabetes, the cumulative effects of hyperglycemia, and a higher prevalence of micro- and macrovascular complications ( 30 , 37 , 38 ). Young and middle-aged adults with DFU tend to present with more advanced ulcer stage and are more likely to have foot infection, hospitalization, and ulcer recurrence than older adults treated in similar settings ( 39 , 40 ). Higher HbA 1c and higher rates of PN and smoking found in young adults with diabetes may account for some of these differences ( 39 , 40 ). Younger adults presenting with DFU tend to represent a phenotype of severe and/or poorly managed disease that warrants special attention to glycemic control and lifestyle modification in this population.

The incidence of DFU is approximately 1.5 times higher among men than women with diabetes ( 30 , 38 , 41 ). The incidences of minor and major amputation are also higher among men, with risk estimates for men ranging from 1.4 to 3.5 times higher in several large studies ( 3 , 42 , 43 ). Sex differences are likely explained by underlying risk factors, access to care, screening, and adherence to treatment. Compliance with therapeutic footwear is similar between men and women despite women’s more negative attitudes about these shoes ( 44 ), but women are more likely to perform recommended self-care and foot care ( 44 ). Men with diabetes have a higher prevalence of PN, PAD, and cardiovascular disease ( 45 ), which together account for a majority of observed sex differences in DFU risk ( 45 ).

Race, Ethnicity, Socioeconomic Status, and Geography

Black, Hispanic, and other non-White groups experience a much higher burden of diabetes than White adults, including a higher burden of DFU ( 35 , 46 ). Socioeconomic and geographic disparities overlap heavily with racial and ethnic disparities in DFU, and the independent effects of these factors are difficult to separate ( 47 – 50 ). Unequal access to care manifests in increased risk of incident DFU ( 51 ). Likelihood of advanced-stage ulcer at diagnosis and risk of hospitalization for DFU are higher among Black and Hispanic adults ( 26 , 36 , 49 ), individuals in the lowest-income categories ( 48 ), those with less comprehensive (or no) insurance ( 36 , 48 ), those with lower education levels ( 33 ), and those who live in socioeconomically deprived neighborhoods ( 36 , 48 , 51 ). Black and Hispanic adults presenting with infection and ischemia are less likely to undergo revascularization than White patients ( 52 , 53 ), and racial minorities and people without insurance are more likely to undergo early (within 1 year) minor or major amputation after incident DFU than White people or people with private insurance ( 49 , 54 , 55 ). These findings suggest that disparities in access to care and biases in practice patterns may each contribute to unequal outcomes ( 26 , 49 , 50 , 56 , 57 ).

High rates of lower-extremity amputation and mortality tend to cluster both within neighborhoods and by region ( 34 , 47 , 58 , 59 ), almost always corresponding to areas with a high density of economically deprived and racial and ethnic minority populations ( 47 ). This layering disadvantage is the consequence of racialized segregation, lack of economic opportunity, and unequal health care that characterize structural racism ( 60 ). Despite significant overlap, racial and ethnic differences in outcomes are not fully attenuated by controlling for socioeconomic or geographic factors ( 47 , 48 , 52 ). While risk for poor outcomes is compounded in people with more than one minority or disadvantaged group status (e.g., rural Black adults) ( 49 ), poor outcomes for minority groups persist despite socioeconomic advantage (e.g., high-income Black adults) ( 52 ). Some patterns, such as unequal revascularization rates in people with ischemic DFU, have been shown to widen among the highest-income Black and White adults ( 52 ). These findings reflect gaps in our ability to measure racial biases within the health system.

Geographic variation in lower-extremity outcomes is well established and is closely linked to socioeconomic status. In the U.S. and U.K., geographic variation accounts for a three- to fivefold difference in rates of incident lower-extremity amputation among adults with diabetes that can only partially be explained by clinical risk factors ( 34 , 59 , 57 ). Differential access to preventive and specialty care ( 59 , 61 ), financial constraints that delay presentation ( 62 ), and provider-specific practices in limb preservation ( 54 ) likely contribute to geographic disparities and to worse outcomes in minority and rural populations ( 49 , 61 ). Some health system-based measures, including managed care plans and Medicaid expansion, have demonstrated modest narrowing of disparities in DFU morbidity ( 26 , 63 ), although dedicated research on interventions to specifically address disparities is lacking.

Glycemic Management

The cumulative burden of hyperglycemia and its causal relationship with microvascular complications are well established ( 64 ). Chronically elevated HbA 1c is an independent risk factor for DFU and for amputation and mortality following DFU ( 37 ). Maintaining a lower HbA 1c delays the progression of microvascular complications of diabetes ( 65 , 66 ) and is associated with decreased risk of amputation in adults with type 1 and type 2 diabetes ( 65 ). Secondary analyses and extended follow-up of landmark trials show dose-response associations between HbA 1c and risk of incident DFU and amputation ( 65 ). Early intensive glucose control may confer reduction in risk of DFU and amputation even during subsequent periods of elevated HbA 1c ( 37 ), signaling a component of “metabolic memory.” These findings underscore the importance of aggressive up-front glucose management in patients with diabetes in decreasing the lifetime risk of DFU.

Overweight, Obesity, and Underweight

The association of obesity with incident DFU has not been consistently demonstrated, and obesity is not associated with incident or recurrent DFU, amputation, or mortality in several recent systematic reviews ( 30 , 38 , 41 , 67 ). In patients who develop DFU, underweight BMI has been linked to an increased risk of amputation and mortality in population- and hospital-based studies ( 17 , 41 ), likely reflecting higher rates of frailty and poor nutrition in the underweight population.

Smoking is associated with an increased risk of PN in adults with diabetes and is an extremely strong risk factor for PAD ( 13 ). Several studies report strong associations of smoking with incident DFU ( 30 ), longer healing time, higher rates of nonhealing DFU ( 18 ), and a subsequent 1.5- to 2.5-fold increased risk of amputation ( 17 , 41 , 43 ). There are minimal data evaluating the impact of smoking cessation on PN progression or risk of lower-extremity amputation in people with DFU, but smoking cessation has been demonstrated to improve 5-year amputation-free survival by up to 20% in individuals with diabetes in PAD cohorts ( 68 ).

Cardiovascular Disease

Cardiovascular disease, including congestive heart failure, coronary artery disease, and stroke, affects up to 30% of people with diabetes globally and is the leading cause of death among people with DFU ( 64 , 69 ). Prospective cohorts demonstrate bidirectional associations between DFU and cardiovascular disease, with incident DFU associated with faster progression of cardiovascular disease ( 69 ), and even subclinical cardiovascular disease conferring increased risk of DFU ( 70 ). Cardiovascular disease is also associated with delayed healing and a higher risk of amputation and mortality ( 4 , 71 ). DFU and cardiovascular disease are both markers of diabetes severity and duration, and they act synergistically on physiologic (e.g., increased inflammatory markers, procoagulable state) and clinical (e.g., loss of functional status) factors that contribute to morbidity ( 72 ). Aggressive management of cardiovascular risk factors is a central goal of multidisciplinary diabetes care and has been shown to decrease risk of DFU occurrence and reduce mortality in people who develop DFU ( 73 ).

Chronic Kidney Disease

Diabetes is a leading global cause of chronic kidney disease (CKD) and the most common cause of end-stage kidney disease ( 74 ). The prevalence of comorbid diabetes and CKD has risen markedly over the past two decades, driven primarily by increasing diabetes prevalence ( 74 , 75 ); an estimated 35–42% of patients with diabetes have some degree of renal impairment ( 46 , 74 , 75 ), and the prevalence of CKD among older adults with diabetes exceeds 50% ( 75 ). Black and Hispanic adults and low-income groups have much higher rates of CKD than White and middle- or high-income groups ( 75 ).

End-stage kidney disease and CKD are linked to higher risk of incident DFU, longer healing time, higher ulcer recurrence rates, and higher rates of lower-extremity amputation ( 76 , 77 ). These associations are strong enough to warrant inclusion of CKD in expert definitions of an at-risk foot even for people without prior DFU or structural deformity. For people with kidney disease, end-stage kidney disease on hemodialysis confers the greatest risk of DFU ( 77 ). Stage 4 CKD is associated with an almost 4-times-increased incidence of DFU and greater than 7-times-increased risk of amputation compared with GFR ≥60 mL/min/1.73 m 2 ( 76 ); even mildly reduced kidney function (eGFR 30–60 mL/min/1.73 m 2 ) is linked with higher risk of incident DFU and amputation ( 76 ). The high prevalence of CKD among racial and ethnic minorities and socioeconomically disadvantaged people contributes to the disproportionate burden of DFU morbidity in these populations.

Retinopathy

There is a strong association between the presence and severity of diabetic retinopathy and DFU. Diabetic retinopathy occurs at two- to fourfold higher rates among adults with DFU than in those without ( 78 ). Severe diabetic retinopathy (including proliferative retinopathy) is also more frequent among adults with DFU than those without, and chronic foot wounds lasting >3 months are associated with more rapid progression of retinopathy ( 79 ). Visual impairment secondary to retinopathy may worsen gait instability and increase risk of foot trauma in those with PN, which can precipitate DFU formation ( 78 ), although the causal mechanisms have not been definitively established. Both DFU and retinopathy are likely signs of advanced microvascular disease that may partially explain this association.

Healing and Recurrence

Ulcer healing is defined as complete epithelialization of a previously ulcerated site ( 22 ). Time from diagnosis to wound healing and overall rates of healing differ widely based on ulcer etiology, size, presence of infection, and patient characteristics, with median healing times ranging from 3 months to more than 12 months ( 7 , 80 ). Ischemic ulcers, larger and deeper ulcers, plantar ulcers, and ulcers with infection are associated with poor or prolonged healing ( 7 , 18 , 81 , 82 ). In addition to wound- and patient-level risk factors described previously, nonambulatory status is associated with prolonged healing and lower amputation-free survival ( 7 , 18 ). There is currently no validated predictive model for DFU healing that includes both patient and wound factors.

The strongest clinical predictor of developing a DFU is a prior DFU or amputation ( 2 ). Recurrence is the occurrence of an ulcer, either at the site of a prior ulcer or at another site, after complete healing ( 5 ). Prospective cohort studies demonstrate 1- and 3- to 5-year recurrence rates from 25% to 44% and 50% to 65%, respectively ( 2 , 39 , 83 ). Contralateral lower-extremity amputation independently increases ulcer recurrence by two- to threefold and shortens the average interval to ulcer recurrence ( 84 ), presumably due to gait alterations. Other factors consistently associated with recurrence are similar to those for nonhealing, although PAD has not been shown to be a strong influence on DFU recurrence despite its effects on primary healing ( 84 ).

Diabetic foot infection affects approximately 60% of DFU and confers a substantial risk of morbidity ( 67 , 69 , 85 ). Infection is a primary driver of emergency department visits and hospitalization in patients with diabetes and with DFU specifically ( 86 , 87 ). Foot ulcer precedes the vast majority of diabetic foot infections, with higher risk of infection in recurrent wounds, long-standing wounds, and wounds that probe to bone, as well as among patients with recent history of prior non–foot infection ( 70 , 85 , 88 ). Relapsed or recalcitrant infection is common; even after debridement, up to 25% of adults with diabetic foot infection will have persistent infection after 10 to 20 days, and modern series show 10% to 45% of patients hospitalized for foot infection require readmission within 1 year ( 89 , 90 ). Among people who develop a diabetic foot infection, the majority will require operative intervention for debridement and 15% to 20% will require amputation for adequate source control or healing ( 69 ). In people with severe infection or osteomyelitis, the amputation rate rises to almost 90% ( 85 ).

Lower-Extremity Amputation

Diabetes is the leading risk factor for lower-extremity amputation in U.S. adults, with an estimated 150,000 diabetes-related major or minor amputations per year ( 46 ). Lifetime risk of any lower-extremity amputation among people with DFU is at least 19% ( 56 ). Overall diabetes-related amputations decreased steadily over the 1990s and 2000s despite rising diabetes prevalence. Over the same time, minor amputation made up an increasing proportion of these amputations, corresponding to higher rates of lower-extremity revascularization procedures; these trends are thought to represent improved efforts at limb preservation ( 91 , 92 ).

After a long period of decline in incidence, several recent studies demonstrate plateaued or increasing incidence of lower-extremity amputation, including major amputation ( 43 ), with some regions experiencing a nearly 50% uptick since 2014 ( 42 , 43 , 46 , 93 ). The overall resurgence in severe morbidity appears to disproportionately affect younger adults and Black and Hispanic groups ( 42 , 53 , 55 , 94 ), which is particularly concerning given the already wide inequities in care for racial and ethnic minorities. Even controlling for DFU incidence, Black and Hispanic adults have lower rates of attempted revascularization, higher rates of failed limb preservation, and higher risk of amputation than White adults ( 49 , 50 , 52 , 53 ). Amputation is a late-stage complication of poor long-term diabetes management, and it often reflects inadequate access to, delivery of, and uptake of diabetes care. The compounding effects of socioeconomic disadvantage, other social determinants of health, and structural racism on marked disparities in amputation rates by race, ethnicity, and socioeconomic status cannot be overstated ( 35 , 60 ).

Survival in people with incident DFU is significantly worse compared with that of similar people with diabetes without foot complications ( 2 , 67 ). Although DFU is a marker of more severe microvascular disease and/or otherwise poor health status, both DFU and any lower-extremity amputation are independent predictors of mortality ( Fig. 4 ) ( 67 , 69 ). A recent meta-analysis comprising almost 125,000 patients in 16 countries reported mortality rates of 13.1% at 1 year, 49.1% at 5 years, and 76.9% at 10 years following incident DFU, with cardiovascular disease and infection representing the leading causes of death ( 67 ). Mortality following diabetes-related amputation is even higher: the estimated five-year mortality is 54% to 79% following minor amputation ( 95 , 96 ) and 53% to 91.7% following major amputation, with notably higher mortality in older adults and those with CKD and PAD ( 19 , 97 , 98 ).

Pathways to ulceration and lower-extremity amputation in DFU.

Diabetes care in the U.S. accounts for an estimated $273 billion in direct and $90 billion in indirect costs annually ( 46 ). Foot complications represent a major source of costs among people with diabetes, leading to higher rates of hospital admission, emergency department visits, outpatient visits and home health care utilization, and excess annual expenditures of 50% to 200% above the baseline cost of diabetes-related care ( 86 ). Advanced-stage ulcers cost upwards of $50,000 per wound episode, and direct costs of major amputation are even higher ( 99 ). These numbers likely underestimate the true economic burden of DFU given out-of-pocket expenses, loss of productivity, and decreased employment associated with DFU ( 86 ).

Guideline-Directed Screening and Management

Prevention and management of diabetic foot complications is a centerpiece of diabetes care. A discussion of best-practice diabetes care is beyond the scope of this review, but many DFU-associated metabolic and cardiovascular risk factors are modifiable in early stages and are addressed by clinical guidelines ( 16 ). Implementation of comprehensive guideline-directed care for patients with diabetes is improving, but rates of adherence to multiple quality indicators are only 50% to 68% in the U.S. and Europe ( 32 ). Achievement of clinical targets is lower, with blood pressure targets met in fewer than 30% of patients and HbA 1c near or below 7.0% in fewer than 45% of patients ( 100 ). Black, Hispanic, Native American/American Indian, and indigenous peoples continue to be significantly less likely than non-Hispanic White groups to receive full guideline-directed care and to achieve guideline-recommended goals ( 32 ), almost certainly contributing to the increased risk of DFU in these populations.

Delayed ulcer presentation predicts poor prognosis ( 7 , 54 , 87 ). Frequent foot exams are fundamental to decreasing incidence and morbidity, and inadequate foot care is associated with higher rates of DFU, LEA, and mortality ( 101 , 102 ). Guidelines for frequency of screening for PN, PAD, and DFU or other preulcerative lesions in the adults with diabetes ( Table 2 ) recommend at least an annual comprehensive foot exam for all patients with diabetes, including inspection, monofilament and tuning fork evaluation for loss of protective sensation, and pulse exam ( 1 , 16 ). Screening exams should be performed every 3–6 months for high-risk patients ( 16 ). The importance of multidisciplinary foot care for high-risk people deserves particular emphasis, especially the involvement of podiatry and vascular surgery ( 45 ).

Professional guidelines for screening and management of patients at risk for DFU

ABI, ankle-brachial index; CVD, cardiovascular disease; ESKD, end-stage kidney disease; LE, lower extremity; LOPS, loss of protective sensation; MDFC, multidisciplinary diabetic foot clinic; T1DM, type 1 diabetes; T2DM, type 2 diabetes; TBI, toe-brachial index; TcPO2, transcutaneous oximetry, (a measure of tissue oxygenation, where normal is >55 mmHg); temp, temperature; TP, toe pressure (usually systolic pressure).

Rates of annual foot exams by a provider in adults with diabetes vary widely ( 32 ). In the U.S., where annual foot exams are a quality metric tied to reimbursement, adherence has been stagnant despite improved achievement of other components of guideline-directed diabetes care ( 32 ). Certain racial and ethnic minority populations (e.g., Hispanic and Asian adults), people without insurance, and socioeconomically disadvantaged populations receive less overall guideline-directed care and are also less likely to report foot exam by a provider in the past year ( 32 , 35 ). The implementation of a hemodialysis center-based monthly foot screening in a U.S. study showed a 17% reduction in subsequent risk of amputation, demonstrating the significant potential effectiveness of screening in high-risk groups ( 103 ). Routine foot screening is critical and low rates of adherence to standards of care for preventing diabetic foot infections is a major concern.

Emerging Modalities for Self-Screening and Early Detection of DFU

Several promising technologies may aid in the early detection of preulcerative or ulcerative foot lesions. Telemedicine-assisted foot examinations have been shown in small studies to be as effective as in-person provider exams at detecting early lesions, with time and cost savings to patients that have promise to reduce existing barriers to care ( 62 , 104 ). Increased temperature is a well-validated preulcerative sign, and clinical trials of temperature-sensing mats ( 105 ) and socks ( 106 ) have been successful in identifying preulcer or DFU weeks earlier than a clinical exam. These passive surveillance technologies may be able to reduce incident DFU through alerts to offload pressure points temporarily or by prompting a thorough foot evaluation. Additional pressure-sensing modalities including insoles may help risk-stratify people with high plantar pressures, monitor for effective offloading before or during DFU episodes, and evaluate progress in gait retraining after DFU healing or amputation ( 107 ). Despite compelling evidence supporting their efficacy and cost effectiveness, these technologies have not been widely adopted.

The detrimental effect of DFU on overall health status and quality of life is well documented, and patient-reported outcomes are increasingly recognized as meaningful measures in diabetic foot care ( 108 , 109 ). People with DFU typically report poor quality of life, primarily in the domain of physical functioning. Persistent ulcers, major amputation, and limited ambulation are associated with worse quality of life for both patients and their caregivers ( 108 , 109 ). Healing, including after minor amputation, is associated with dramatic improvement in self-reported physical functioning, and people with healed DFU have overall self-reported quality of life near the norms for populations without diabetes ( 109 ).

Though qualitative studies consistently identify fear, anxiety, frustration, isolation, and sadness as common emotional responses to the diagnosis of DFU, few studies have demonstrated differences in psychosocial quality of life related to DFU ( 109 ). DFU-specific measures have been proposed to better assess the social and emotional consequences of active ulcers and should be considered when evaluating patient-reported outcomes.

DFU is a common complication of diabetes that has been aptly compared with cancer in terms of chronicity, recidivism, cost, and burden ( 97 ). Major clinical risk factors for DFU are PN, PAD, and foot deformities, but race, ethnicity, socioeconomic status, and geography are powerful mediators of risk for DFU and lower-extremity amputation. The consequences of first ulceration—poor quality of life, recurrence, major amputation, and death—are significant, but this morbidity is not reflected in the funding allocated for DFU-related research, which totals less than 0.2% of total federal spending on diabetes ( 97 ).

Complications of DFU can be attenuated by guideline-directed screening, early diagnosis, and aggressive medical management of diabetes and cardiovascular disease. Ineffective population-based screening, limited access to preventive care, and delays in access to diabetes, vascular, and podiatry specialist care contribute to late-stage ulcer presentation and, thus, to poor prognosis. Rising lower-extremity amputation rates among young and middle-aged adults with diabetes and persistent racial, ethnic, and socioeconomic disparities reflect these gaps in care.

Major efforts are needed to develop health system-wide improvements in DFU prevention and early diagnosis, especially in disadvantaged populations. Funding should be prioritized for high-quality population-based registries to track DFU incidence, prevalence, outcomes, and process measures. Initiatives to expand use of effective at-home screening modalities and allocate resources for more frequent provider foot exams in regions where major amputation rates are high have the potential to reduce DFU incidence and morbidity in the most at-risk populations. Dedicated research on racial and socioeconomic differences in timing of care, limb preservation, and amputation are necessary to identify and address factors perpetuating structural bias and disparate outcomes. Significantly more public and institutional funding for DFU research and care initiatives is warranted to correct the imbalance between current resource allocation and the enormous burden of DFU. Ultimately, a paradigm shift toward DFU prevention and health equity is required to produce meaningful reductions in DFU, major lower-extremity amputation, and mortality.

Acknowledgments. We acknowledge the contributions of Caroline Wang (Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD) and Alana Keegan (Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD) in creating and editing figures and tables.

Funding. C.H. was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant K23 DK124515. L.S. was supported by NIH National Heart, Lung, and Blood Institute grant K24 HL152440. This work was also supported by NIH NIDDK grant R01 DK089174 to L.S.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. K.M. completed literature review and wrote the manuscript. M.F. and A.J.M.B. reviewed and edited the manuscript. E.S. and C.W.H. were involved in the conception of this work and reviewed and edited the manuscript. All authors approved of the final version of the manuscript. K.M. and C.W.H. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Diabetic ulcer.

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• Continuing Education Activity

Diabetes mellitus is a metabolic endocrine disorder due to an overall deficiency of insulin (Type 1) or defective insulin function (Type 2) which causes hyperglycemia. Type 1 diabetes which is usually seen in younger patients accounts for 5% to 10% of cases worldwide and is secondary to autoimmune destruction of B-islet cells of the pancreas. Type 2 diabetes accounts for 90% to 95% of cases worldwide and is due to genetic and environmental factors with resultant insulin resistance and pancreatic beta-cell dysfunction. Complications arising from hyperglycemia can either be macrovascular or microvascular. The macrovascular disease affects mainly the cardiovascular and cerebrovascular systems, and the microvascular disease includes nephropathy, retinopathy, and neuropathies. A debilitating complication of diabetes mellitus is diabetic ulcers, which leads to increased overall morbidity in patients. This complication may be prevented, as the inciting factor is most often minor trauma. Early identification of these cutaneous injuries also can lead to improved outcomes while decreasing the risk of progression. Patients with diabetes mellitus (type 1 or 2) have a total lifetime risk of a diabetic foot ulcer complication as high as 25%. This activity reviews the evaluation and management of diabetic ulcers and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.

• Recall the cause of diabetic ulcer.
• Describe the stages of a diabetic foot.
• Summarize the treatment of diabetic ulcer.
• Outline the evaluation and management of diabetic ulcers and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.
• Introduction

Diabetes mellitus is a metabolic endocrine disorder due to an overall deficiency of insulin (Type 1) or defective insulin function (Type 2) which causes hyperglycemia. Type 1 diabetes which is usually seen in younger patients accounts for 5% to 10% of cases worldwide and is secondary to the autoimmune destruction of insulin-producing B-islet cells of the pancreas which results in complete insulin deficiency.  Type 2 diabetes accounts for 90% to 95% of cases worldwide and is due to genetic and environmental factors with resultant insulin resistance and pancreatic beta-cell dysfunction causing relative insulin deficiency. This form of diabetes remains clinically inevident for many years. Although abnormal glucose metabolism which is associated with chronic hyperglycemia results in complications that can either be macrovascular or microvascular. The macrovascular disease affects mainly the cardiovascular and cerebrovascular systems, and the microvascular disease includes nephropathy, retinopathy, and neuropathies.

A debilitating complication of diabetes mellitus is diabetic ulcers, which leads to increased overall morbidity in patients. This complication may be prevented, as the inciting factor is most often minor trauma. Early identification of these cutaneous injuries also can lead to improved outcomes while decreasing the risk of progression. Patients with diabetes mellitus (type 1 or 2) have a total lifetime risk of a diabetic foot ulcer complication as high as 25%.   [1]

The Six Stages of a Diabetic Foot as described by the 7th Practical Diabetes International Foot Conference 

• Stage 1 - Normal foot with no risk factors;
• Stage 2 - High-risk foot
• Stage 3 - Ulcerated foot
• Stage 4 - Cellulitic foot
• Stage 5 - Necrotic foot
• Stage 6 - Foot that cannot be rescued

There are three types of diabetic foot ulcer described namely neuropathic, neuroischaemic, and ischaemic. [2]   [3]   Sensory neuropathy leads to the majority of ulcers as a result of minor trauma which is not perceived by the patient and further goes untreated as there are no associated pain symptoms unless there is a routine evaluation to assist in identification.  [4] Myocardial infarction is one of the most significant events related to peripheral arterial disease increased risk of ischemia. However, ischemia leading to diabetic ulcers adds severe morbidity and health care cost as it can be a chronic complication which is difficult to treat as there is insufficient blood supply.

Major Risk Factors  [5]

• Peripheral motor neuropathy: Abnormal foot anatomy and biomechanics, with clawing of toes, high arch, and subluxed metatarsophalangeal joints, leading to excess pressure, callus formation, and ulcers
• Peripheral sensory neuropathy: Lack of protective sensation, leading to unattended minor injuries caused by excess pressure or mechanical or thermal injury
• Peripheral autonomic neuropathy: Deficient sweating leading to dry, cracking skin
• Neuro-osteoarthropathy deformities (i.e., Charcot disease) or limited joint mobility
• Abnormal anatomy and biomechanics, leading to excess pressure, especially in the midplantar area
• Vascular (arterial) insufficiency: Impaired tissue viability, wound healing, and delivery of neutrophils
• Hyperglycemia and other metabolic derangements: Impaired immunological (especially neutrophil) function and wound healing and excess collagen cross-linking 
• Epidemiology

The pooled worldwide prevalence of diabetic foot ulceration was 6.3%. North America had the highest prevalence of 13%; Oceania had the lowest prevalence of 3%. The prevalence in Africa was 7.2% which was higher than Asia 5.5%. Diabetic foot ulceration was more prevalent in male patients with diabetes mellitus, 4.5%, than female patients, 3.5%. Patients with type 2 diabetes mellitus (T2DM) had a higher prevalence of ulceration at 6.4% compared to patients with type 1 diabetes mellitus (T1DM), 5.5%.  [6] [7]

In a systematic review and meta-analysis by Zhang et al. published in 2016, patients with diabetic foot ulceration had the following characteristics: older age (61.7 plus or minus 3.7 versus 56.1 plus or minus 3.9), longer diabetic duration (11.3 plus or minus 2.5 versus 7.4 plus or minus 2.2), lower body mass Index (BMI, 23.8 ± 1.7 versus 24.4 plus or minus 1.7), higher percentage of smokers (29.1%, 95%CI: 18.3% to 39.8% versus 17.4%, 95% CI: 12.4% to 22.4%), hypertension (63.4%, 95%CI: 49.4% to 88.3% versus 53.1%, 95%CI: 33.8% to 72.5%), and diabetic retinopathy (63.6%, 95%CI: 38.8% to 88.3%% versus 33.3%, 95%CI: 13.8% to 52.7%) than patients that did not develop diabetic foot ulceration. 

• Pathophysiology

Atherosclerosis and diabetic peripheral neuropathy are the two main causes leading to a complication of diabetes such as ulcers. Atherosclerosis leads to decreased blood flow in large and medium-sized vessels secondary to thickening of capillary basement membrane, loss of elasticity, and deposition of lipids within the walls. Further arteriosclerosis leads to small vessel ischemia. Peripheral neuropathy affects the sensory, motor, and autonomic nervous system. There are multifactorial causes such as vascular disease occluding the vasa nervorum, endothelial dysfunction, chronic hyperosmolarity, and effects of increased sorbitol and fructose. 

• History and Physical

The evaluation of patients presenting with diabetic ulcers can be divided into a clinical and radiologic assessment.

A clinically pertinent history of the type of diabetes, medication history, comorbidities, symptoms of peripheral neuropathy, and vascular insufficiency should be elucidated. Symptoms of neuropathy include hypoesthesia, hyperesthesia, paresthesia, dysesthesia, and radicular pain. Vascular insufficiency has varying presentations and most patients are asymptomatic. However, they can present with intermittent claudication, rest pain, and healing or non-healing ulcers.

In the examination of the legs and foot, an inspection should be performed in a well-lit room with appropriate exposure. Proper documentation using descriptions of ulcer characteristics with size, depth, appearance, and location performed. Presence of discoloration, necrosis, or areas of drainage are signs of infection, and further care is required. Other abnormalities such as nail discoloration, callus formation, and deformities should be noted. Imbalance in the innervations of the foot muscles from neuropathic damage can lead to the development of common deformities seen in affected patients. Hyperextension of the metatarsal-phalangeal joint with interphalangeal or distal phalangeal joint flexion leads to hammer toe and claw toe deformities, respectively. Charcot arthropathy is a commonly seen deformity. Assessment of footwear is important as it can be a contributing factor to the development of foot ulceration. The presence of callus or nail abnormalities should be noted. 

Examine the cardiovascular system, checking popliteal, posterior tibial, and dorsalis pedis pulse. Claudication, loss of hair, and the presence of pale, thin, shiny, or cool skin are physical findings suggestive of potential ischemia. If a vascular disease is a concern, the evaluator should measure the ankle-brachial index (ABI). ABIs can, however, be falsely elevated in patients with diabetes mellitus due to calcification of vessels. More reliable methods of assessing the potential for healing foot ulcers in patients with diabetes mellitus suspected of having peripheral ischemia involve systolic toe pressure measurements by photoplethysmography or measurement of distal transcutaneous oxygen tension. 

Based on wound depth and necrotic tissue, diabetic ulcers can be classified by the Wagner ulcer classification system.  [8] [9] [10]

Wagner-Meggitt Classification of Diabetic Foot

• Grade 0 - Foot symptoms like pain, only
• Grade 1 - Superficial ulcers involving skin and subcutaneous tissue
• Grade 2 - Deep ulcers involving ligaments, muscles, tendons, etc
• Grade 3 - Ulcer with bone involvement  
• Grade 4 - Forefoot gangrene
• Grade 5 - Full-foot gangrene

Serum Inflammatory Markers

X-Ray/Ultrasound:  Performed for the detection of the spread of the lesion and soft tissue involvement.

MRI:  Radiologic evaluation involves plain radiographs in two-thirds of the views assessing for deformity . If there is suspicion of osteomyelitis, tendonitis, or joint inflammation MRI imaging should be performed.

Probe-to-bone Test

Monofilament Test

Bone Scan:  Can identify the involvement of deep wounds.

Biopsy and Culture:  Specimen of bone and other tissue involved and histopathological examination is performed with the culture. This can also guide antibiotic treatment in case of a bacterial infection.

• Treatment / Management

Multimodal Diabetic Ulcer Management [11] [12]

• Patient Education: Education on foot care, as well as control of blood sugar levels, should be performed early. This can also be done with the aid of diabetic educators and social workers. 
• Blood-Sugar Control: This is managed using a team approach of primary care physician, podiatry, and vascular specialist and based on the severity of the disease and the patient’s attitude toward medication, especially insulin. 
• Decreasing Pressure , preventing further or new trauma: Offloading pressure to the area can be done with crutches, wheelchairs, and casting. Ulcer healing is improved with total contact casting, irremovable cast walkers compared to removable cast walkers.  [13]
• Improve Peripheral Vascular Circulation: Antiplatelet agents are the initial drug therapy; however, insufficiency requires surgical bypass. 
• Prevent or Control Infection: Systemic and source control is achieved using antibiotics and surgical debridement.  
• Topical Ulcer Care:   Principles of wound care include the use of topical agents with dressing and debridement. Shallow ulcers can be managed with occlusive and semi-occlusive dressings. A specialized dressing containing hyaluronic acid, collagen, and surgical intervention for debridement is usually required in full-thickness ulcers.
• Differential Diagnosis
• Venous Ulcers:  It is caused by chronic elevation of venous pressure leading to incompetent valves. Venous blood from deep veins refluxes into superficial veins causing varicose veins and lower limb edema.Leakage of plasma proteins and leukocytes causing edema and free radical damage to the tissue resulting in ulcer formation. The most common locations are the pretibial area and above the medial malleolus. Usually, a shallow ulcer with irregular borders and overlying fibrinous exudate is present.
• Diabetic Dermatopathy:  These are purplish, round asymptomatic lesions that usually occur in the lower extremities but can be present anywhere on the body of diabetic patients. These lesions usually require no intervention.  
• Malignancy:- Different malignancies can present as cutaneous ulcers but systemic signs and symptoms ( fever, weight loss, malaise, etc) are also usually present. The diagnosis can be confirmed by microscopic examination of the biopsy specimen.
• Superficial Thrombophlebitis:  Characterized by pain, erythema, tenderness overlying inflamed and thrombosed superficial veins.
• Leukocytoclastic Vasculitis:  Inflammation of blood vessels and surrounding tissues caused by the deposition of immune complexes.
• Gouty Arthritis:  Monosodium urate crystal deposits in joints can result in inflammation, usually associated with hyperuricemia.
• Infection:  Primary infectious ulcer results either by direct inoculation or systemic spread. Clinical features vary with the types of infection.
• Sickle Cell Disease:  Sickle cell disease can result in painful leg ulcers commonly on medial and lateral malleoli.
• Drugs:- Some drugs e.g, warfarin, heparin, hydroxyurea can result in ulcer formation.

The prognosis of diabetic ulcers is dependant on various factors such as strict diabetes control, patient education, a healthy lifestyle, and proper wound care. Poor blood supply, infection, prolonged duration, and recurrent ulcers are associated with poor prognosis. These prognostic indicators are utilized to take necessary interventions and precautionary measures to reduce the risk of severe complications such as osteomyelitis and amputation. [14] [15]

• Complications

 Diabetic ulcers can lead to many complications and are responsible for hospitalizations and functional disabilities in diabetic patients. [16]

• Ascending lymphangitis
• Osteomyelitis
• Limb ischemia
• Amputation [17] [18]
• Postoperative and Rehabilitation Care

Proper debridement, wound irrigation and dressing care are necessary for the prevention of infection and healing. Off-loading in patients with diabetic foot ulcers by total contact casts and postoperative shoes is an effective measure for promoting wound healing. In diabetic patients, postoperative care is of even greater importance in the presence of various risk factors such as impaired mobility, decreased perfusion, malnutrition, and reduced sensation. [19]

• Consultations

Early detection and treatment can help in decreasing complications. Timely interventions  and consultations with the following are recommended: [20]

• Endocrinologist
• Infectious disease specialist
• Vascular surgeon
• Orthopedic surgeon 
• Plastic surgeon
• Deterrence and Patient Education

Patient education about the proper care of wounds and the risk of recurrence is necessary to improve the quality of life of the patients. Reducing hospital visits and increasing the ulcer-free duration is the goal. Long term surveillance and information sharing can maximize the results of the care provided. Sharing articles written in plain and easy to understand language is the key to successful communication. Health care providers should be encouraged to provide necessary information available on various platforms. [21]

• Pearls and Other Issues

Diabetes can lead to serious complications if they are not identified and managed adequately. Diabetic ulcers are a common complication of uncontrolled diabetes. The frequency of these complications can be lowered by controlling blood glucose, self-examination of feet, and regular check-ups by doctors.

The following are some risk factors associated with diabetic foot ulcers:-

• Abnormality of foot anatomy(e.g Charcot arthropathy)
• Poor blood circulation(e.g weak pulse, cold skin, or blue skin)
• Abnormality of peripheral sensations(e.g inability to sense pain in diabetic neuropathy)
• Smoking can reduce circulation to the feet.

Different measures can be taken to reduce the risk of foot problems. In general, keeping blood glucose in the target range reduces all kinds of diabetic complications. This involves making a healthy diet and lifestyle changes. Avoiding activities associated with foot injuries and avoiding smoking can be helpful. Caring for nails and trimming them straight across to avoid skin injury. Washing feet and choosing socks and shoes wisely. Regular foot exams to avoid unnoticed injuries. [22]  

• Enhancing Healthcare Team Outcomes

The management of a diabetic ulcer is very difficult and is best done with a team that includes an endocrinologist, surgeon, wound care nurse, internist, physical therapist, vascular surgeon, an infectious disease expert, and dietitian. Besides ensuring that glucose levels are controlled, one has to ensure that the tissue has an adequate blood supply. All diabetics should be urged to stop smoking and resume an exercise program. Close follow up is required by an interprofessional team as these ulcers can rapidly lead to necrosis and loss of a digit or a limb. Diabetic ulcers and wounds should be evaluated by a standardized and evidence-based approach. Well established communication and coordination among the health providers can significantly decrease complications such as amputation. [23] [24]

• Review Questions
• Access free multiple choice questions on this topic.
• Comment on this article.

Diabetic Ulcer Due to neuropathy, vasculopathy, and foot deformity. Note periwound callous formation. Wagner Grade 2 Contributed by Mark A. Dreyer, DPM, FACFAS

Diabetic Foot Ulcer. Neuropathic ulceration in a patient with diabetes. Note periwound callous formation. Wagner Grade 2 Contributed by MA Dreyer, DPM, FACFAS

Jodhpur Technique. Depiction of success of the technique in a non-healing foot ulcer of a patient with diabetes with diabetic foot (diabetes controlled with HbA1C < 6.5 X one year). (A) Baseline multiple ulcers over the foot involving (more...)

Disclosure: Corrine Packer declares no relevant financial relationships with ineligible companies.

Disclosure: Syed Awab Ali declares no relevant financial relationships with ineligible companies.

Disclosure: Biagio Manna declares no relevant financial relationships with ineligible companies.

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• Cite this Page Packer CF, Ali SA, Manna B. Diabetic Ulcer. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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SYSTEMATIC REVIEW article

A systematic review of diabetic foot infections: pathogenesis, diagnosis, and management strategies.

• 1 Department of Physiology, Neuroscience, and Behavioral Sciences, St. George’s University School of Medicine, St. George’s, Grenada
• 2 Department of Microbiology, St. Matthews University School of Medicine, Grand Cayman, Cayman Islands
• 3 Department of Anatomy, St. Matthews University School of Medicine, Grand Cayman, Cayman Islands
• 4 Department of Medical Education, School of Medicine, The University of Texas Rio Grande Valley, Edinburg, TX, United States
• 5 Department of Pathology, St. Matthews University School of Medicine, Grand Cayman, Cayman Islands

Background: Diabetic foot infection represents a significant complication of diabetes mellitus, contributing substantially to morbidity, mortality, and healthcare expenditure worldwide. Accurate diagnosis relies on a comprehensive assessment integrating clinical evaluation, imaging studies, and microbiological analysis. Management necessitates a multidisciplinary approach, encompassing surgical intervention, antimicrobial therapy, and advanced wound care strategies. Preventive measures are paramount in reducing the incidence and severity, emphasizing patient education, regular foot screenings, and early intervention.

Methods: The researchers performed a systematic review of literature using PUBMED MESH keywords. Additionally, the study was registered in the International Prospective Register of Systematic Reviews at the Center for Reviews and Dissemination, University of York (CRD42021277788). This review provides a comprehensive overview of the microbial spectrum and antibiotic susceptibility patterns observed in diabetic foot infections.

Results: The search through the databases finally identified 13 articles with 2545 patients from 2021 to 2023. Overall, the predominant Gram-positive microbial species isolated were Staphylococcus aureus, Enterococcus fecalis, Streptococcus pyogenes, Streptococcus agalactiae, and Staphylococcus epidermidis. Whereas the predominant Gram-negative included Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa.

Conclusion: Diabetic foot infections represent a complex and multifaceted clinical entity, necessitating a holistic approach to diagnosis, management, and prevention. Limited high-quality research data on outcomes and the effectiveness of guideline recommendations pose challenges in updating and refining existing DFI management guidelines.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021277788 , identifier CRD42021277788.

Introduction

Diabetic foot infections (DFIs) represent a complex and challenging complication of diabetes mellitus, presenting a significant burden on healthcare systems worldwide. These infections, primarily triggered by neuropathy and vascular complications associated with diabetes, often lead to severe consequences such as tissue damage, limb amputation, prolonged hospitalization, and increased mortality rates. Understanding the microbiological profile and antibiotic sensitivity patterns of organisms causing DFIs is crucial in guiding appropriate therapeutic interventions and improving clinical outcomes for affected individuals.

Roughly 18.6 million individuals worldwide experience diabetic foot ulcers annually, with 1.6 million cases reported in the United States alone. These ulcers precede 80% of lower extremity amputations in individuals diagnosed with diabetes and are correlated with heightened mortality rates ( 1 ). The pathophysiology of DFIs is intricately linked to the underlying microvascular and neuropathic complications of diabetes mellitus. Peripheral neuropathy, characterized by sensory loss and motor impairment, predisposes individuals to foot deformities and altered biomechanics, increasing the risk of pressure injuries and ulcer formation ( 2 ). Concurrent peripheral arterial disease exacerbates tissue ischemia, impairing wound healing and creating a favorable environment for infection ( 1 ). The interplay between these factors underscores the importance of preventive foot care strategies and early intervention to mitigate the risk of DFIs and their sequelae.

Microbiologically, DFIs encompass a diverse array of pathogens, with Staphylococcus aureus emerging as a predominant causative organism across various studies ( 3 ). However, the microbial profile of DFIs exhibits considerable heterogeneity, influenced by factors such as geographic location, patient demographics, and local antimicrobial resistance patterns. Recent research has highlighted the growing incidence of multidrug-resistant organisms, including Pseudomonas aeruginosa and MDR gram-negative bacilli, posing significant challenges for empirical antibiotic therapy ( 3 ). Understanding the microbial epidemiology of DFIs is essential for guiding antimicrobial stewardship efforts and optimizing treatment outcomes.

Clinically, the diagnosis of DFIs relies on a combination of clinical, biochemical, and radiographic findings to accurately assess the extent and severity of infection ( 4 ). While bone biopsy remains the gold standard for diagnosing osteomyelitis, its invasive nature and potential complications limit its routine use in clinical practice. Consequently, clinicians often rely on a combination of advanced imaging modalities, such as magnetic resonance imaging (MRI) and computed tomography (CT), alongside deep tissue cultures to guide therapeutic decisions effectively. Timely and accurate diagnosis is paramount to initiate appropriate management promptly and prevent further complications, including limb loss and systemic spread of infection.

Management of DFIs necessitates a multidisciplinary approach, encompassing surgical intervention, antimicrobial therapy, and comprehensive wound care to address the complex nature of these infections ( 4 ). Surgical debridement plays a pivotal role in source control and removal of necrotic tissue, particularly in cases of deep or severe infections. In osteomyelitis, surgical resection of infected bone may be curative, reducing the risk of recurrent infection and subsequent amputation. Antimicrobial therapy should be tailored to the individual patient and guided by culture and susceptibility testing to optimize outcomes and minimize the risk of antibiotic resistance. Additionally, comprehensive wound care, including off-loading strategies and advanced dressings, is essential for promoting wound healing and preventing recurrence.

Preventive measures play a crucial role in reducing the incidence and severity of DFIs, emphasizing the importance of patient education, regular foot assessments, and early intervention ( 2 ). Identifying high-risk individuals and implementing targeted interventions, such as diabetic foot care clinics and structured foot care programs, can significantly reduce the burden of DFIs and their associated complications. Furthermore, ongoing research efforts focusing on novel diagnostic modalities, antimicrobial therapies, and wound healing strategies hold promise for advancing the management of DFIs and improving clinical outcomes for individuals with diabetes-related foot complications.

Recent advancements in medical research have emphasized the need for a comprehensive evaluation of the microbial spectrum involved in DFIs and their susceptibility to various antibiotics. A myriad of studies, as evidenced by the systematic review conducted herein, have endeavored to elucidate the intricate relationship between diabetic foot infections and antimicrobial resistance patterns. This review synthesizes data from 13 pertinent articles obtained through meticulous searches across PubMed and other reputable databases, aiming to provide a consolidated perspective on the prevailing microbial flora in diabetic foot infections and the evolving trends in antibiotic susceptibility.

In this context, understanding the epidemiology, microbiology, and antibiotic resistance profiles of organisms causing DFIs is pivotal for optimizing therapeutic strategies, facilitating early intervention, and curtailing the escalating global burden of diabetic foot complications. This review article aims to critically analyze and synthesize the existing literature to offer a comprehensive overview of the microbial spectrum and antibiotic susceptibility patterns observed in diabetic foot infections, ultimately contributing to enhanced clinical management practices.

Materials and methods

The researchers adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) protocols ( 5 , 6 ). Additionally, the study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) at the Center for Reviews and Dissemination, University of York (CRD42021277788), before the project commenced.

Search strategy

Previous research has reviewed and summarized the antimicrobial resistance pattern in diabetic foot infection patients in South Asia between 2016 and 2021 ( 7 ). Therefore, published studies worldwide were searched in PubMed (US National Library of Medicine, National Institutes of Health) for potentially relevant studies from 2021 up to 2023. Articles published in English were included. The authors were required to reach a consensus among themselves on the final search strategy. The medical subject headings (MeSH) search terms included “Drug Resistance, Microbial,” “Diabetic Foot” and “Diabetes Mellitus” including all subheadings. The search strategy included (“Diabetic Foot”[Mesh]) AND “Drug Resistance, Microbial”[Mesh]. Finally, the relevant articles were also included by adopting the snowball method which involves searching the bibliographic list of selected articles.

Selection of studies

Two independent reviewers (SN and NN) screened the retrieved papers based on titles and abstracts. Criteria for examination of full text of the relevant paper after the initial database screening were as follows:

Articles reporting data on Drug Resistance, Microbial,” “Diabetic Foot” and “Diabetes Mellitus that could be extracted for systematic review were included. Original studies conducted in any geographical location that provided a comprehensive overview of the microbial spectrum and antibiotic susceptibility patterns observed in diabetic foot infections were included in the final analysis.

The non-peer-reviewed editorials, letters, commentaries, incomplete data, reviews, conference posters, preprints, and thesis were excluded.

Any confusion or doubts regarding the study selection were resolved by reaching a consensus. The full PRISMA flow diagram outlining the study selection process is available in Figure 1 .

Figure 1 Represents the process of study selections for the systematic review as per the PRISMA protocol.

Data extraction

The authors extracted the relevant data, and the data was cross-checked. In a blank Excel sheet, data on year, authors, region, age range of patients, total included patients number, most prevalent pathogens, resistance pattern of Gram positive and Gram negative bacteria, and Study’s Focus were extracted.

Quality assessment of included studies

The quality of the studies was assessed using the JBI Critical Appraisal Tool for Analytical cross sectional studies ( 8 ). All of the 13 included studies received at least 5 “YES” answers and were included in the systematic review synthesis ( Table 1 ).

Table 1 Quality assessment of studies using JBI’s Critical Appraisal Tools designed for Analytical Studies.

Search results and study characteristics

Our search through the databases finally identified 13 articles on diabetic foot infection and antibiotic resistance patterns that were included in the systematic review from 2021 to 2023. The article exclusion criteria included the following reasons:

Not relevant to the objective

Not in line with the inclusion criteria

The full-text pdf was not available

Not original research

No availability of statistical results

A detailed synthesis of included studies is provided in Table 2 .

Table 2 A detailed qualitative synthesis of included studies.

The microbiological Profile of Diabetic Foot Infections and the antibiotic resistance patterns were explored from the included studies. Overall, the predominant Gram-positive microbial species isolated in DFIs were Staphylococcus aureus, Enterococcus fecalis, Streptococcus pyogenes, Streptococcus agalactiae, and Staphylococcus epidermidis. Whereas the predominant Gram-negative included Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa.

The antibiotic resistance patterns for the most common Gram-positive and Gram-negative species are listed in Table 3 .

Table 3 Shows the antibiotic resistance patterns for the most common Gram-positive and Gram-negative species.

DFIs represent a complex and multifaceted clinical entity, necessitating a holistic approach to diagnosis, management, and prevention. By integrating existing research findings with insights from clinical practice, this review provides a comprehensive overview of DFIs, highlighting the challenges and opportunities for optimizing patient care and reducing the burden of this debilitating complication of diabetes mellitus. We set out to explore the antimicrobial resistance patterns amongst the patients of DFIs worldwide, and our results indicate the most prevalent bacteria. The most common Gram-positive and Gram-negative bacteria associated with DFI were Staphylococcus aureus and Escherichia coli, respectively.

Pathogenesis and diagnosis of DFIs

The pathogenesis of DFIs is multifactorial, primarily driven by the underlying complications of diabetes, including peripheral neuropathy, peripheral arterial disease, and impaired immune function. Peripheral neuropathy leads to sensory loss and motor abnormalities, increasing the risk of unnoticed trauma and skin breakdown. Vascular compromise further impairs wound healing and predisposes individuals to infections. The presence of high blood glucose levels in diabetes also promotes bacterial growth and impairs immune responses, creating an environment conducive to infection development. These factors collectively contribute to the high incidence of DFIs in individuals with diabetes ( 4 ).

Diagnosing diabetic foot infections involves a thorough clinical assessment, including evaluating signs of inflammation, such as erythema, warmth, swelling, and purulent discharge. Diagnostic imaging modalities like X-rays and advanced imaging techniques may be utilized to assess for soft tissue involvement and osteomyelitis. Laboratory tests, such as elevated inflammatory markers like C-reactive protein and erythrocyte sedimentation rate, can aid in confirming the presence of infection. Additionally, microbiological cultures of wound samples help identify the causative pathogens, guiding appropriate antibiotic therapy. A multidisciplinary approach involving healthcare professionals specializing in wound care, infectious diseases, and podiatry is essential for the accurate diagnosis and effective management of diabetic foot infections to prevent complications and improve patient outcomes ( 4 ).

In recent years, advanced diagnostic techniques have been increasingly utilized for challenging cases of diabetic foot infections (DFIs) to improve accuracy and guide appropriate management. Molecular diagnostics, such as polymerase chain reaction (PCR) and next-generation sequencing (NGS), allow for the rapid and precise identification of microbial pathogens in DFIs. These molecular methods can detect a wide range of bacteria, including fastidious and anaerobic organisms, providing valuable information for targeted antimicrobial therapy ( 22 ). Advanced imaging techniques, such as magnetic resonance imaging (MRI) with contrast enhancement and positron emission tomography-computed tomography (PET-CT) scans, offer enhanced sensitivity and specificity in detecting soft tissue infections, osteomyelitis, and deep-seated abscesses. These modalities help in the accurate localization of infections and assessment of treatment response ( 23 ). Additionally, point-of-care testing, which includes rapid diagnostic tests for detecting specific pathogens or antibiotic resistance genes, is being developed to facilitate prompt decision-making regarding antimicrobial therapy. These tests enable healthcare providers to tailor treatment regimens based on the individual’s infection profile, leading to more effective outcomes ( 24 ). By incorporating these advanced diagnostic techniques into clinical practice, healthcare professionals can achieve earlier and more precise diagnoses of challenging cases of DFIs, leading to targeted and personalized treatment strategies that optimize patient care and outcomes.

Antimicrobial resistance in DFIs

Analyzing two decades of research on antimicrobial resistance reveals a remarkable 450% surge in research activity from 1999 to 2018, with over 150,000 articles originating from 166 countries ( 25 ). Antibiotic resistance patterns and various resistance trends have been observed among members of Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis both temporally and globally. Among Enterobacteriaceae, the production of extended-spectrum beta-lactamases stands out as a common resistance mechanism ( 26 ). Notably, for Pseudomonas aeruginosa, there has been a significant decreasing trend in resistance rates to ciprofloxacin, ceftazidime, meropenem, and imipenem. This decline in resistance rates could potentially be attributed to reduced usage of ciprofloxacin among Pseudomonas aeruginosa isolates ( 27 ). Several factors can explain the decreased resistance of Pseudomonas aeruginosa to meropenem and imipenem. Changes in antibiotic utilization within healthcare settings can significantly impact the development of resistance. A shift towards more judicious prescribing of meropenem and imipenem may have decreased resistance rates over time ( 28 ). Furthermore, implementing antibiotic stewardship programs, which aim to optimize antibiotic use, promote appropriate prescribing practices, and prevent the emergence of resistance, likely play a crucial role in this observed trend ( 29 ). The evolution of bacterial strains is another important factor. P. aeruginosa is known for its rapid adaptation and evolution. Strains with lower intrinsic resistance to meropenem and imipenem may have become more prevalent, leading to an overall decrease in resistance rates ( 30 ). Additionally, environmental factors, such as changes in healthcare environments or exposure to different antimicrobial agents, can also influence the resistance patterns of P. aeruginosa over time ( 31 ).

Several antibiotics approved for treating various infections demonstrate potential efficacy in managing DFIs. For DFIs caused by Staphylococcus aureus, ceftaroline, dalbavancin, oritavancin, and tedizolid show promise. In cases of DFIs due to Pseudomonas aeruginosa and Enterobacteriaceae, several combination therapies have demonstrated effectiveness. These combinations include ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and cefiderocol. Additionally, meropenem/vaborbactam and plazomicin can be utilized for infections caused by Enterobacteriaceae ( 32 ).

Diabetic foot infection stands as a primary contributor to non-traumatic lower limb amputations. However, pertinent data are scarce, and there is a notable absence of randomized controlled trials assessing the efficacy of these agents in this domain. Pending the availability of more substantial evidence, cefiderocol and dalbavancin, having undergone more comprehensive examination in patients with bone infections, could present appealing choices for carefully chosen individuals with severe diabetic foot infection ( 32 ). Several factors have been identified as risk factors in the development of antimicrobial resistance in DFI. These include high BMI, high glycosylated hemoglobin, elevated fasting blood glucose, course and size of the ulcer, peripheral neuropathy, and vascular disease. Also, compromise of the host’s immune system due to a decrease in leukocyte count and neutrophil ratio was identified ( 33 ). Most common bacteria in DFIs are Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, and Morganella morganii, all of which demonstrated antibiotic resistance to various medications including Ampicillin, Ciprofloxacin, Levofloxacin, Trimethoprim-sulfamethoxazole, and Cefuroxime. Among these antibiotics, Escherichia coli showed the most resistance ( 34 ). Even as gram negative bacteria have been implicated as the most common cause of DFIs, the most notable risk factors are hypertension and neuropathy. Also, the overuse of antibiotics has been found to play a role in the development of these drug resistant infections ( 35 ). These gram-negative bacteria were also isolated from patients with foot ulcers that have had an amputation. The most notable being Escherichia coli ( 36 ).

A study examined diabetic foot osteomyelitis and identified both gram positive and gram negative pathogens in bone cultures. These organisms included coagulase negative Staphylococcus, Staphylococcus aureus, Proteus species, Pseudomonas aeruginosa, and Escherichia coli. Although cultures were mostly polymicrobial, they were either gram-positive dominated or gram negative dominated. Penicillin without β-lactamase resistance was found in both cases, but sulphonamides were peculiar to gram negative dominated ( 37 ). In another study done in sub-Saharan Africa, Staphylococcus aureus showed the highest pooled resistance toward gentamicin and ciprofloxacin. E. coli and Klebsiella pneumoniae showed significant resistance rates for several common antibiotics ( 38 ).

In the case of polymicrobial infections in DFI, determining the specific species responsible for the infection can be challenging due to multiple microorganisms. Several factors contribute to the complexity of identifying the causative agent in polymicrobial infections. Firstly, synergistic interactions among microbial species can lead to enhanced virulence or antibiotic resistance, making it difficult to isolate and attribute the infection to a single organism ( 39 ). Additionally, the microbial composition of polymicrobial infections can vary between individuals and even within the same individual over time, complicating the identification of the primary pathogen responsible for the infection ( 40 ). Furthermore, conventional diagnostic methods may not always accurately identify all microorganisms present in a polymicrobial infection. Some organisms may be fastidious or difficult to culture, leading to underestimating their role in the infection ( 41 ). Lastly, many microorganisms in polymicrobial infections can form biofilms, protecting against antibiotics and host immune responses. Biofilms can consist of multiple species, further complicating the identification of the dominant pathogen ( 42 ). Host factors, including immune status, comorbidities, and anatomical factors, can also influence the microbial composition of polymicrobial infections. The host response to infection may also impact the relative abundance and pathogenicity of different microorganisms ( 43 ).

Given the challenges in identifying the responsible species in polymicrobial infections, a holistic approach to managing such infections is crucial. Comprehensive microbial analysis techniques, such as next-generation sequencing or metagenomic approaches, can offer a more detailed understanding of the microbial community dynamics. By acknowledging these complexities and limitations, researchers and clinicians can develop more effective treatment strategies that address the diverse microbial populations in polymicrobial infections.

Risk factors for DFIs

The observed high antibiotic resistance risk associated with factors such as high BMI, elevated HbA1c levels, elevated fasting blood glucose, and the course and size of the ulcer in DFIs underscores the intricate relationship between host characteristics and microbial susceptibility to antibiotics. High BMI is known to be associated with chronic inflammation and impaired immune function, creating a favorable environment for microbial proliferation and antibiotic resistance. The increased adipose tissue in individuals with high BMI can serve as a reservoir for pathogens, leading to persistent infections and reduced antibiotic efficacy ( 33 ). Elevated HbA1c levels and fasting blood glucose contribute to the impaired immune response and delayed wound healing commonly observed in individuals with poorly controlled diabetes. The hyperglycemic environment promotes bacterial growth and biofilm formation, enhancing antibiotic resistance ( 33 ). The course and size of the ulcer in DFIs indicate the severity and chronicity of the infection. Larger and more chronic ulcers often harbor diverse microbial populations, including antibiotic-resistant strains. The presence of biofilms in chronic ulcers further complicates treatment and contributes to antibiotic resistance ( 42 ).

Host factors, including immune status, comorbidities, and anatomical factors, can influence the microbial composition of polymicrobial infections. The host response to infection may also impact the relative abundance and pathogenicity of different microorganisms ( 43 ). By elucidating the association between these host-related factors and antibiotic resistance in DFIs, the current review highlights the importance of comprehensive management strategies that address not only the microbial aspect but also the host factors influencing treatment outcomes. Future research focusing on personalized approaches considering individual patient characteristics and tailored antibiotic regimens may offer insights into mitigating the impact of antibiotic resistance in DFIs.

Recent research on DFIs highlights risk factors such as previous hospitalization, ulcer size, surgical therapy, and C-reactive protein. Regarding previous hospitalization, nosocomial infections are well-established culprits and arise due to the poor state of the wards and faulty antiinfection policies and procedures. For ulcers, ulcer size is an important prognostic factor in diabetic foot. An ulcer size >4cm 2 is said to be a significant risk factor for DFIs. As regards surgical therapy (like amputation), the exact way it increases the risk of MDR remains unclear. A unique feature of surgical therapy is that it alters the biomechanics of the foot. For C-reactive protein, its increased level during bacterial infections is a risk factor for MDR DFI ( 11 ). Among infections severely endangering the affected limb, cultures most commonly identify pathogens such as Staphylococcus aureus, Enterococcus, facultative gram-negative bacilli, and group B streptococci; with the unhygienic nature of the hospital wards responsible for exaggerating the infections ( 44 ). Apart from previous history of antimicrobial exposure, wounds due to neurovascular defects, Wagner grade 3–5, and concurrent osteomyelitis are risk factors for AMR ( 45 ). Considering the high prevalence of antibiotic resistance in Escherichia coli and Klebsiella pneumoniae towards most antibiotics, policies, processes, and procedures must be implemented to ensure good hygiene and infection control to mitigate or eliminate the spread of these organisms ( 38 ).

The prevalence of AMR changed with onset of the Covid-19 pandemic, with a 3-fold increase in risk from the pre-pandemic period. Some factors responsible in studied population were antibiotic self-administration, prior hospitalization, and antibiotic prescription by general practitioners ( 46 ). In a hospital in Nicaragua, previous antibiotic usage was identified as a key contributor to the high prevalence of MRSA as well as the resistance rate exhibited by gram-negative organisms to various classes of antibiotics ( 47 ). Contrary to the above studies, another study revealed that the administration of antibiotics to patients with diabetic foot osteomyelitis up to a week prior to biopsy does not affect the culture result. Furthermore, such administration does not result in increased antibiotic resistance ( 48 ). Also, although recurrent episodes of DFI are likely to follow a successfully treated episode, the treatment does not increase the likelihood of AMR in these episodes ( 49 ).

Clinical implications and treatment strategies

The MDT approach has proven effective in reducing DFUs and LEAs, yet there exists variability among team members and interventions. Podiatrists are proposed as pivotal in DFU prevention and management. A recent systematic review assessing podiatric interventions in MDTs for DFUs and LEAs, has emphasized the need for intervention clarity and role delineation in practice and literature ( 50 ). Another systematic review including thirty-three studies, aimed to evaluate how multidisciplinary teams impact major amputation rates among DFI patients. The MDT was structured to include a blend of medical and surgical disciplines, ensuring a comprehensive approach to diabetic foot ulcer management. Larger teams found organizational benefits by designating a “captain” and establishing a core team structure supplemented by ancillary members. This setup facilitated clear referral pathways and streamlined care algorithms, enabling timely and thorough management of diabetic foot ulcers. Multidisciplinary teams addressed a range of key tasks, including glycemic control, local wound management, vascular disease, and infection, ensuring a holistic approach to patient care. Notably, 94% of studies reported reduced major amputation rates with multidisciplinary teams, highlighting their effectiveness in addressing key aspects of diabetic foot care ( 51 ).

In 2019, led by the Jiangsu Medical Association and the Diabetes Society of the Chinese Medical Association, a writing group was convened for the development of the ‘Guidelines on Multidisciplinary Approaches for the Prevention and Management of Diabetic Foot Disease (2020 edition)’. These guidelines enlisted contributions from experts spanning endocrinology, burn injury, vascular surgery, orthopedics, foot and ankle surgery, and cardiology. They stress the criticality of timely wound assessment, diagnosis, and appropriate surgical interventions, both internally and externally, in managing diabetic foot pathology. The article strongly advocates for the establishment of multidisciplinary diabetic foot teams and specialist centers at various levels, underlining the urgency of prompt consultation or referral to these teams or centers based on the severity of the patient’s condition ( 52 ). A retrospective study on a multidisciplinary team led by internists revealed promising outcomes in diabetic foot ulceration management. The study encompassed 315 patients, with 207 treated during the pre-multidisciplinary period and 108 during the multidisciplinary period. Significant reductions in major amputations and bloodstream infections were observed during the multidisciplinary period compared to the pre-multidisciplinary phase (10% vs. 14%; p = 0.01 and 2% vs. 13%, p = 0.04, respectively). Moreover, there was a notable decrease in 30-day mortality rates (5% vs. 11%, p = 0.08) and a substantial increase in vascular interventions (18% vs. 1%, p < 0.01). Improvements in diabetes control were evident, with lower median glucose levels recorded (163 vs. 185 mg/dl, p = 0.03). Treatment modifications, including updates to medications such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and statins, were implemented alongside enhanced disease control indicated by improved laboratory results at discharge, including albumin and CRP levels ( 53 ).

Challenges in developing and adopting guidelines for DFI management

The development and adoption of guidelines for the proper management of DFIs on a global scale face several hindrances that impede their effectiveness and implementation. Some of the key challenges include variability in healthcare systems and resources across different regions, which poses a challenge in standardizing guidelines for DFI management. Disparities in access to healthcare facilities, diagnostic tools, and antimicrobial agents hinder the uniform implementation of guidelines ( 54 ). Insufficient awareness among healthcare providers, patients, and caregivers about the importance of following guidelines for DFI management can lead to suboptimal adherence. Additionally, inadequate education and training programs on evidence-based practices contribute to the underutilization of guidelines ( 54 ).

Resource-constrained settings, especially in low- and middle-income countries, face challenges in implementing comprehensive DFI management guidelines due to limited infrastructure, lack of essential medications, and inadequate funding for healthcare services. Also, the complexity and length of guidelines for DFI management may deter healthcare providers from incorporating them into routine clinical practice. Guidelines that are overly detailed or difficult to interpret can lead to confusion and non-compliance ( 55 ). Effective management of DFIs often requires a multidisciplinary approach involving podiatrists, infectious disease specialists, endocrinologists, and wound care nurses. The lack of collaboration and communication among different healthcare professionals can hinder the implementation of guideline recommendations ( 54 ). Limited high-quality research data on DFI management outcomes and the effectiveness of guideline recommendations pose challenges in updating and refining existing guidelines. The lack of robust evidence-based practices can hinder the development of comprehensive and up-to-date guidelines ( 55 ).

Addressing these hindrances through targeted strategies such as capacity building, educational initiatives, simplified guideline formats, enhanced collaboration among healthcare professionals, and increased research efforts can help overcome barriers to the development and adoption of guidelines for the proper management of DFIs on a global scale ( 54 , 55 ).

Future perspectives and recommendations

Despite significant advancements in the management of DFIs, several gaps in current knowledge and research limitations persist, hindering optimal patient care and outcomes. One notable limitation is the lack of evidence-based guidelines guiding the choice and efficacy of topical treatments for DFIs. The choice of topical approaches, whether alone or as adjuncts to systemic antibiotics, is often not evidence-based due to a paucity of robust clinical trials ( 56 ). This gap underscores the need for well-designed studies to evaluate the efficacy and comparative effectiveness of various topical agents, including antibiotic-impregnated biomaterials, novel antimicrobial peptides, and photodynamic therapy. Furthermore, research emphasizes the need for clear evidence-based guidelines on the use of topical treatments in DFI management ( 57 ). Despite the increasing prevalence of antibiotic resistance, there is a lack of consensus on the optimal topical interventions to limit the use of systemic antibiotics and prevent disease progression. This highlights the urgent need for well-designed clinical trials to assess the efficacy, safety, and cost-effectiveness of emerging topical therapies. Another significant gap in current research lies in the understanding of antimicrobial resistance patterns and their impact on clinical outcomes in patients with DFIs. Previous research highlights the prevalence of multidrug-resistant organisms (MDROs) in DFIs, including methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae ( 17 ). However, the study also underscores the need for appropriate empirical antimicrobial therapy, as higher rates of reinfection and major amputation were found even with the use of broad-spectrum antimicrobials. This emphasizes the importance of tailored antibiotic stewardship programs to optimize treatment outcomes while minimizing the risk of antimicrobial resistance.

Future research directions in understanding and combating antibiotic resistance in diabetic foot infections (DFIs) should focus on several key areas to address current challenges and optimize treatment outcomes. Firstly, there is a critical need for further investigation into the mechanisms of antimicrobial resistance in DFIs, including the identification of novel resistance mechanisms and the factors contributing to the emergence and spread of multidrug-resistant organisms (MDROs). Understanding the antimicrobial resistance patterns of pathogens is crucial for guiding empirical antibiotic therapy and minimizing treatment failures ( 17 ). Secondly, future research should focus on the development and evaluation of novel antimicrobial agents and treatment modalities for DFIs. This includes exploring alternative therapeutic approaches such as antimicrobial peptides, growth factors, and nanomedicine ( 58 ). Novel treatment modalities with broad-spectrum activity and low potential for inducing resistance could offer promising alternatives to conventional antibiotics and help mitigate the spread of antimicrobial resistance. Additionally, there is a need for well-designed clinical trials to evaluate the efficacy, safety, and cost-effectiveness of emerging antimicrobial therapies in DFIs. Comparative effectiveness studies comparing different treatment modalities and assessing long-term outcomes, such as wound healing, infection recurrence, and amputation rates, are essential for guiding clinical decision-making and optimizing patient care. Furthermore, future research should explore innovative strategies for antibiotic stewardship and infection control in DFIs. This includes implementing antimicrobial stewardship programs in healthcare settings, promoting judicious antibiotic use, and optimizing infection prevention and control practices to minimize the risk of antimicrobial resistance and healthcare-associated infections.

Effective strategies to mitigate antibiotic resistance in diabetic foot infections (DFIs) require a multifaceted approach involving both clinical practice and public health policies. Based on the current evidence and research findings, several recommendations can be made to address this pressing issue. Firstly, healthcare providers should prioritize judicious antibiotic prescribing practices in the management of DFIs. Inappropriate initial antibiotic treatment is associated with higher rates of reinfection and major amputation. Therefore, clinicians should adhere to evidence-based guidelines and perform comprehensive microbiological evaluations to guide empirical antibiotic therapy and minimize the risk of antimicrobial resistance. Furthermore, healthcare facilities should implement antimicrobial stewardship programs to promote responsible antibiotic use and optimize treatment outcomes in DFIs. These programs should involve multidisciplinary teams, including infectious disease specialists, microbiologists, pharmacists, and infection control practitioners, to develop and implement evidence-based guidelines, educate healthcare providers, and monitor antibiotic prescribing practices. In addition to clinical practice, public health policies are crucial in mitigating antibiotic resistance in DFIs. Governments and healthcare authorities should prioritize investments in the research and development of novel antimicrobial agents, as well as promote initiatives to incentivize antibiotic research and development, such as push funding mechanisms ( 56 ). Moreover, efforts should be made to enhance surveillance of antimicrobial resistance and healthcare-associated infections, including DFIs, through national and global surveillance systems. This includes monitoring antimicrobial resistance patterns, identifying emerging resistance trends, and implementing targeted interventions to prevent and control the spread of resistant pathogens.

Diabetic foot infections constitute a multifaceted clinical condition, requiring a comprehensive approach to diagnosis, management, and prevention. Overall, in the current study, the predominant Gram-positive microbial species isolated in DFIs were Staphylococcus aureus, Enterococcus fecalis, Streptococcus pyogenes, Streptococcus agalactiae, and Staphylococcus epidermidis. Whereas the predominant Gram-negative included Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa. Risk factors for antimicrobial resistance in DFI encompass higher BMI, HbA1c, blood glucose levels and also ulcer characteristics, neuropathy, and vascular disease. MDT approach reduces DFIs with variation in team composition and podiatrists are crucial for DFI prevention and management. Addressing research limitations in DFI management through trials and collaborations is crucial. Future research on antibiotic resistance should focus on understanding mechanisms, developing agents, and stewardship. Recommendations include judicious prescribing, stewardship programs, R&D, and surveillance to combat resistance effectively and improve outcomes.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

NN, SM, SN: Writing – original draft, Writing – review & editing, Validation, Investigation, Formal analysis. AJ, NL, NA: Writing – review & editing, Validation, Investigation, Formal analysis. DB, AA-I, KT: Writing - review & editing. SN, SM: Conceptualization, Project administration, Writing - original draft, Methodology, Supervision, Writing - review & editing. AC, YG, DB, AA-I: Writing - review & editing. SM, NL, NN: Contributed equally and share first authorship.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: diabetic foot infection, antimicrobial resistance, podiatry, gram negative (G -) bacteria, gram positive (G +) bacteria

Citation: Maity S, Leton N, Nayak N, Jha A, Anand N, Thompson K, Boothe D, Cromer A, Garcia Y, Al-Islam A and Nauhria S (2024) A systematic review of diabetic foot infections: pathogenesis, diagnosis, and management strategies. Front. Clin. Diabetes Healthc. 5:1393309. doi: 10.3389/fcdhc.2024.1393309

Received: 02 April 2024; Accepted: 17 July 2024; Published: 06 August 2024.

Reviewed by:

Copyright © 2024 Maity, Leton, Nayak, Jha, Anand, Thompson, Boothe, Cromer, Garcia, Al-Islam and Nauhria. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Samal Nauhria, [email protected]

† These authors have contributed equally to this work and share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Factors contributing to the presentation of diabetic foot ulcers

Affiliation.

• 1 Department of Diabetes and Endocrinology, City Hospital, Nottingham, UK.
• PMID: 9371480
• DOI: 10.1002/(SICI)1096-9136(199710)14:10<867::AID-DIA475>3.0.CO;2-L

We have undertaken a prospective study of the presentation of all 669 ulcers seen in a specialist multidisciplinary foot clinic between 1 January 1993 and 1 August 1996, with particular reference to the factors which precipitated ulceration as well as to any delays in referral. Nearly two-thirds (61.3%) of all lesions were first detected by the patient or a relative, and the remainder by a healthcare professional. The median (range) time which elapsed between ulcer onset and first professional review was 4 (0-247) days, and the median time between first review and first referral to the specialist clinic was 15 (0-608) days. Significant delays were judged to have occurred in 39 instances. The most common precipitant of ulceration was rubbing from footwear, which was responsible for 138 (20.6%). Fifty-eight (8.7%) were the result of immobilization from other illness, and a further 24 were the consequence of surgery. Overall, professional factors contributed to the development or deterioration of 106 lesions (15.8% total). These results should form the basis of strategies designed to minimize the onset of ulceration in those known to be at risk: educational strategies need to be directed at professionals as much as at patients.

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Research Promises Better Diabetic Retinopathy Management

Manuela Callari

August 16, 2024

STOCKHOLM — At the American Society of Retina Specialists (ASRS) 2024 Annual Meeting , researchers discussed how insights into potential risk factors and new treatments could improve outcomes for patients with diabetic retinopathy .

Jennifer Lim, MD, an ophthalmologist and director of the Retina Service at the University of Illinois Hospital & Health Sciences System in Chicago, told Medscape Medical News that emerging approaches to treating diabetic retinopathy offer hope because they address the root causes of the disease beyond just targeting vascular endothelial growth factor (VEGF). She said innovative methods and add-on treatments could lead to more durable and effective drugs.

Exploration of risk factors and treatment options for diabetic retinopathy could lead to more effective management strategies for the condition, agreed David Boyer, MD, an ophthalmologist at Retina Vitreous Associates Medical Group in Los Angeles, speaking with Medscape Medical News .

Risk Factors for Diabetic Retinopathy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon -like peptide 1 receptor agonists (GLP-1 RAs) have gained popularity because of their benefits beyond glycemic control, including weight loss, and cardiovascular and kidney protection. However, the impact of these medications on vision-threatening retinal complications is not fully understood. "There has always been a question about whether these newer diabetes medications might exacerbate diabetic eye disease," said Boyer.

In a retrospective observational study, researchers included adults with type 2 diabetes and moderate cardiovascular disease risk who had no history of advanced diabetic retinal complications. These patients initiated treatment with GLP-1 RA, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas. The study used inverse probability of treatment weighting to mimic randomization and compared the time to the first treatment for diabetic macular edema or proliferative diabetic retinopathy across the treatment groups.

Results, presented by Andrew J. Barkmeier, MD, an associate professor of ophthalmology at the Mayo Clinic, showed that among 371,698 patients, those who initiated therapy with SGLT2 inhibitors had a lower risk of requiring treatment for sight-threatening retinopathy compared with those using other medication classes. GLP-1 RA did not increase retinopathy risk relative to dipeptidyl peptidase 4 inhibitors and sulfonylurea medications.

"[This study] told us that we do have to keep an eye on patients' retinopathy when they start on these new inhibitors. But the progression is minimal and, overall, I think most people today favor keeping blood sugar levels as good as possible," said Boyer, who was not involved in the study.

Another factor that might increase diabetic retinopathy progression is obstructive sleep apnea . This underdiagnosed condition is linked to several health issues, including dementia, stroke , and myocardial infarctions. Although not easily treated, obstructive sleep apnea is manageable, Boyer explained.

Researchers utilized the TriNetX electronic health records research network to identify patients with nonproliferative diabetic retinopathy, both with and without obstructive sleep apnea. 

The results , presented by Ehsan Rahimy, MD, a retinal specialist at Palo Alto Medical Foundation and a professor at Stanford University, showed that patients with obstructive sleep apnea had a significantly higher risk of progressing to proliferative diabetic retinopathy and developing new-onset diabetic macular edema. These patients were more likely to require ocular interventions, such as intravitreal injections and laser photocoagulation. They also had greater risks for stroke, myocardial infarction , and death compared with those who did not have obstructive sleep apnea.

"It was good to bring this to everybody's attention," said Boyer, who was not involved in the study. "It's an easy question to ask someone if they snore."

New Treatments on the Horizon

In another presentation, Nathan C. Steinle, MD, of California Retina Consultants, presented a study that assessed the durability of response to sozinibercept in patients with retinal vascular diseases. This novel therapeutic agent is designed to inhibit VEGF-C and VEGF-D in conditions where VEGF-A suppression alone is insufficient. 

Sozinibercept was combined with standard anti–VEGF-A therapies such as ranibizumab or aflibercept. It involved a prospective, post hoc analysis of two phase 1b, open-label, dose-escalation studies, including 40 patients with neovascular age-related macular degeneration (nAMD) (31 patients) or diabetic macular edema (nine patients). These patients, either treatment-naive or previously treated, received three intravitreal injections of ranibizumab or aflibercept in combination with sozinibercept at various doses.

Results indicated that sozinibercept combination therapy was well tolerated, with no dose-limiting toxicities. In treatment-naive nAMD patients, the mean best-corrected visual acuity (BCVA) improved significantly from baseline at months 3 and 6. Previously treated nAMD patients also showed BCVA improvements, although to a lesser extent. For patients with persistent diabetic macular edema, switching to sozinibercept plus aflibercept resulted in notable BCVA gains. The mean time to requiring retreatment was longer in treatment-naive patients than in those previously treated, indicating a durable response. 

"Combination therapy with sozinibercept is going to be really important," said Lim, who was not involved in the study, "because it attacks with a dual mechanism of action."

Oral agents promise a potentially easier alternative for patients compared with frequent injections. CU06-1004 is a novel orally administered endothelial dysfunction blocker that has shown promise in stabilizing damaged capillaries, reducing abnormal angiogenesis, and inhibiting inflammatory activation in preclinical studies. "CU06 is very interesting to me because by preventing endothelial loss, it gets to the pathophysiology of why the blood vessels break down," Lim said.

In a proof-of-concept phase 2a, multicenter, open-label, parallel-group trial, investigators randomly assigned 67 patients with diabetic macular edema to receive 100 mg, 200 mg, or 300 mg of CU06-1004 once daily for 12 weeks, followed by a 4-week follow-up. 

Results presented by Victor Gonzalez, MD, of Valley Retina Institute in Texas, indicated that the oral agent improved BCVA, stabilized central subfield thickness, and showed positive anatomical changes in optical coherence tomography images. CU06-1004 was well tolerated, with no drug-related serious adverse events. 

"The number [of patients] was very small, and we will need a much longer, larger trial to see if [CU06-1004] has benefits long term," said Boyer, who was not involved in the study. "But I think we're all very excited if we can find an oral agent for treating diabetic retinopathy. It would be easier for the patient to take a pill than having to come in for injections." 

The sustained-release axitinib implant, OTX-TKI, is also generating significant interest, particularly for non-proliferative diabetic retinopathy. Axitinib, a tyrosine kinase inhibitor (TKI), targets signaling pathways crucial in cellular processes, providing a novel approach to managing diseases where traditional therapies might fall short. Unlike traditional anti-VEGF treatments that focus solely on cytokine levels, TKIs block the activation of signaling pathways, preventing downstream signaling regardless of cytokine levels. This mechanism is particularly important because it effectively inhibits disease progression even if levels of VEGF are high, Lim explained.

In the phase 1 HELIOS trial, OTX-TKI was assessed in patients with nonproliferative diabetic retinopathy. This multicenter, double-masked, parallel-group clinical study included 21 patients who had not received anti-VEGF treatment, dexamethasone intravitreal implants in the previous 12 months, or intraocular steroid injections in the prior 4 months. Patients were randomly assigned to receive either OTX-TKI or sham treatment.

Results presented by Dilsher S. Dhoot, MD, of California Retina Consultants, indicated that OTX-TKI was generally well tolerated, with no serious ocular adverse events. At 48 weeks, 46.2% of eyes treated with OTX-TKI showed a 1- or 2-step improvement on the Diabetic Retinopathy Severity Scale (DRSS) compared with none in the sham arm. Additionally, no eyes treated with OTX-TKI experienced a worsening on the DRSS, whereas 25% of eyes in the sham arm did. Vision-threatening complications, such as proliferative diabetic retinopathy or diabetic macular edema, developed in 37.5% of the sham group but in none of the OTX-TKI treated eyes. A single injection of OTX-TKI provided durable DRSS improvement for up to 48 weeks, with no patients in either arm requiring rescue therapy.

"This is a really exciting add-on treatment," Lim said, who was not involved in the study. She explained that it is initially necessary to control the disease with standard treatments, because TKIs may take longer to exhibit their effects. Once the disease is stabilized, TKIs can be used alongside other therapies, potentially reducing the reliance on frequent anti-VEGF injections. "These are preliminary results, but that's the hope going forward."

Lim and Boyer report no relevant financial relationships.

Manuela Callari is a freelance science journalist who specializes in human and planetary health. Her words have been published in The Medical Republic, Rare Disease Advisor, The Guardian, MIT Technology Review, and others.

Send comments and news tips to [email protected] .

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